Oral squamous cell carcinoma (OSCC) is one of the most prevalent and fatal cancer types in the world which causes million death each year. Although surgery combined with chemotherapy or radiotherapy could effective remove OSCC tumor, high recurrence and poor prognosis of recurrent OSCC still surfer the cancer patients. Prodigiosin (PG) is a bacterial-sourced red pigment which has been proved as an anticancer chemical against various cancers e.g. OSCC, lung cancer, breast cancer, etc. Moreover, PG could improve cytotoxicity from paclitaxel against breast cancer. Hence, this study explored the enhancing potency in PG combined with doxorubicin (Dox) against OSCC cells and further uncovered the underlying mechanism. Additionally, putative toxic alteration in liver, kidney, and heart was evaluated in PG/Dox combination, too. Three OSCC cell lines, OECM1, SAS, and FaDu, and 3 normal cell lines, FL83B, HK-2, and h9c2 were performed in the whole study. While PG-primed OSCC cells, Dox could cause higher cytotoxicity in OSCC cells through activating apoptotic (SAS and FaDu) and autophagic (OECM1) cell death. The unveiled mechanism indicated that PG-priming improved Dox accumulation via 2 approaches: raising Dox influx through drug importers (FaDu) which was not associated with recent known Dox importer and reducing Dox metabolic pathway (OECM1 and SAS) which was proved by overexpressing Dox metabolic gene AKR1A1 and NQO1, respectively. In the other hand, PG-priming increased cytotoxicity from Dox in 3 normal cell lines, which potentiating range was less than OSCC. Underlying mechanism indicated that PG/Dox induced cell death increase was either associated with Dox metabolism reduction nor Dox influx. Taking all results together, PG showed inspiring potency for improving Dox’s anticancer efficacy against OSCC cells. PG/Dox combination could apply in OSCC treatment and popularized to other cancer therapy, especially the cancer which used Dox as first-line chemotherapy.

Motivation and aims 1
Chapter 1 Introduction 3
Chapter 2 Literature review 5
2.1 Prodigiosin 6
2.1.1 Physical and chemical properties 6
2.1.2 Natural source and optimizing production 6
2.1.3 Bioactivity and known action mechanism 7
2.2 Oral cavity cancer (OCC) and oral squamous cell carcinoma (OSCC) 9
2.2.1 Disease progression and epidemiology of OCC 9
2.2.2 Etiology of OCC 10
2.2.3 Conventional treatment strategies for OCC 10
2.3 Doxorubicin 11
2.3.1 General properties and action mechanism 11
2.3.2 Pharmacodynamic/pharmacokinetics information of doxorubicin 11
2.3.3 Doxorubicin chemoresistance 12
2.4. Chemotherapy-induced toxicity 12
2.4.1 General information of chemotherapy-induced toxicity 13
2.4.2 Doxorubicin toxicity 13
2.5 Synergistic effect 15
2.5.1 Overview of synergism and current adjuvant therapy in cancer therapy 15
2.5.2 Acting mechanism of chemotherapeutic synergism 16
2.5.3 Natural compounds as chemotherapeutic adjuvant 17
2.5.4 Detection of synergism within multiple drugs system 18
Chapter 3 Material and methods 21
3.0 Framework 22
Part 1 Evaluation of cytotoxic synergism in PG/Dox combination in OSCC cells 25
3.1.1 Reagents 26
3.1.2 Cell culture 26
3.1.3 Cytotoxicity assay 27
3.1.4 Cell cycle analysis 27
3.1.5 Oxidative stress determination 28
3.1.6 Doxorubicin flux analysis 28
3.1.7 Autophagic flux identification 29
3.1.8 Western blotting 29
3.1.9 Gene overexpression 30
3.1.10 Statistical analysis 31
Part 2 Assessment of hepato-, nephro-, and cardiotoxicity in PG/Dox combination 33
3.2.1 Reagents 34
3.2.2 Cell culture 34
3.2.3 Cytotoxicity assay 34
3.2.4 Cell cycle measurement 34
3.2.5 Overexpression and recovery assay 34
3.2.6 ROS content analysis 34
3.2.7 Western blotting 35
3.2.8 Statistical analysis 35
Chapter 4 Results 37
Part 1 Evaluation of cytotoxic synergism in PG/Dox combination in OSCC cells 39
4.1.1 Synergistic pattern of PG/Dox combination 40
4.1.2 Identification of cell death characteristics 41
4.1.3 Doxorubicin flux affected by PG-induced autophagy 43
4.1.4 Determination of ROS content in PG-priming OSCC cells 44
4.1.5 Metabolic alteration of Dox metabolism in PG-primed OSCC cells 45
4.1.6 Evaluation of known autophagy trigger in activating PG-induced autophagy 46
Part 2 Toxic assessment of PG/Dox synergism in hepatic, cardiac, and nephrotic approaches 49
4.2.1 Assessment of cytotoxicity in PG/Dox combination 50
4.2.2 Assessment of autophagy in PG/Dox synergism against normal cells 51
4.2.3 Cell cycle alteration after PG/Dox synergism 51
4.2.4 ROS change in normal cells after PG/Dox treatment 52
4.2.5 Dox influx regulation in normal cell after PG/Dox treatment 53
4.2.6 PG/Dox synergism in Dox metabolism in normal cells 53
Chapter 5 Discussion 55
5.1 Known Dox sensitizer 56
5.2 PG as a chemotherapy sensitizer 57
5.3 PG-priming affects Dox flux with unknown factors 58
5.4 PG as an autophagy inducer 59
5.5 Dox as an autophagic inducer 60
5.6 Genetic polymorphism in commercial cells 61
5.7 Unexpected behavior of PG/Dox combination coupled with metabolic inhibitors 61
5.8 Natural Dox enhancer via reducing Dox metabolism 62
Chapter 6 Conclusion and perspective 65
Chapter 7 Future work 67
Chapter 8 Reference 69
Chapter 9 Tables 103
Chapter 10 Figures 125
Appendix I Curriculum vitae 163
Appendix II Publications 169

1. Hajdu, S.I. A note from history: landmarks in history of cancer, part 1. Cancer 2011, 117, 1097-1102, doi:10.1002/cncr.25553.
2. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394-424, doi:10.3322/caac.21492.
3. Ngamkham, S.; Holden, J.E.; Smith, E.L. A Systematic Review: Mindfulness Intervention for Cancer-Related Pain. Asia Pac J Oncol Nurs 2019, 6, 161-169, doi:10.4103/apjon.apjon_67_18.
4. Borges, E.L.; Franceschini, J.; Costa, L.H.; Fernandes, A.L.; Jamnik, S.; Santoro, I.L. Family caregiver burden: the burden of caring for lung cancer patients according to the cancer stage and patient quality of life. J. Bras. Pneumol. 2017, 43, 18-23, doi:10.1590/S1806-37562016000000177.
5. Pai, M.P.; Cottrell, M.L.; Kashuba, A.D.M.; Bertino, J.S. 19 - Pharmacokinetics and Pharmacodynamics of Anti-infective Agents. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), Bennett, J.E., Dolin, R., Blaser, M.J., Eds. Content Repository Only!: Philadelphia, 2015; https://doi.org/10.1016/B978-1-4557-4801-3.00019-9pp. 252-262.e252.
6. Pingili, R.B.; Pawar, A.K.; Challa, S.R.; Kodali, T.; Koppula, S.; Toleti, V. A comprehensive review on hepatoprotective and nephroprotective activities of chrysin against various drugs and toxic agents. Chem. Biol. Interact. 2019, 308, 51-60, doi:10.1016/j.cbi.2019.05.010.
7. Songbo, M.; Lang, H.; Xinyong, C.; Bin, X.; Ping, Z.; Liang, S. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol. Lett. 2019, 307, 41-48, doi:10.1016/j.toxlet.2019.02.013.
8. Hu, D.X.; Withall, D.M.; Challis, G.L.; Thomson, R.J. Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products. Chem. Rev. 2016, 116, 7818-7853, doi:10.1021/acs.chemrev.6b00024.
9. Stankovic, N.; Senerovic, L.; Ilic-Tomic, T.; Vasiljevic, B.; Nikodinovic-Runic, J. Properties and applications of undecylprodigiosin and other bacterial prodigiosins. Appl. Microbiol. Biotechnol. 2014, 98, 3841-3858, doi:10.1007/s00253-014-5590-1.
10. Tenconi, E.; Guichard, P.; Motte, P.; Matagne, A.; Rigali, S. Use of red autofluorescence for monitoring prodiginine biosynthesis. J. Microbiol. Methods 2013, 93, 138-143, doi:10.1016/j.mimet.2013.02.012.
11. Drink, E.; Dugourd, P.; Dumont, E.; Aronssohn, N.; Antoine, R.; Loison, C. Optical properties of prodigiosin and obatoclax: action spectroscopy and theoretical calculations. Phys. Chem. Chem. Phys. 2015, 17, 25946-25955, doi:10.1039/c5cp01498k.
12. Arivizhivendhan, K.V.; Mahesh, M.; Boopathy, R.; Swarnalatha, S.; Regina Mary, R.; Sekaran, G. Antioxidant and antimicrobial activity of bioactive prodigiosin produces from Serratia marcescens using agricultural waste as a substrate. J. Food Sci. Technol. 2018, 55, 2661-2670, doi:10.1007/s13197-018-3188-9.
13. Yildiztekin, F.; Nadeem, S.; Erol, E.; Yildiztekin, M.; Tuna, A.L.; Ozturk, M. Antioxidant, anticholinesterase and tyrosinase inhibition activities, and fatty acids of Crocus mathewii - A forgotten endemic angiosperm of Turkey. Pharm. Biol. 2016, 54, 1557-1563, doi:10.3109/13880209.2015.1107746.
14. Sajjad, W.; Ahmad, S.; Aziz, I.; Azam, S.S.; Hasan, F.; Shah, A.A. Antiproliferative, antioxidant and binding mechanism analysis of prodigiosin from newly isolated radio-resistant Streptomyces sp. strain WMA-LM31. Mol. Biol. Rep. 2018, 45, 1787-1798, doi:10.1007/s11033-018-4324-3.
15. Boric, M.; Danevcic, T.; Stopar, D. Prodigiosin from Vibrio sp. DSM 14379; a new UV-protective pigment. Microb. Ecol. 2011, 62, 528-536, doi:10.1007/s00248-011-9857-0.
16. Han, L.; Zhou, Y.; Huang, X.; Xiao, M.; Zhou, L.; Zhou, J.; Wang, A.; Shen, J. A multi-spectroscopic approach to investigate the interaction of prodigiosin with ct-DNA. Spectrochim. Acta. A Mol. Biomol. Spectrosc. 2014, 123, 497-502, doi:10.1016/j.saa.2013.11.088.
17. Rastegari, B.; Karbalaei-Heidari, H.R.; Yousefi, R.; Zeinali, S.; Nabavizadeh, M. Interaction of prodigiosin with HSA and beta-Lg: Spectroscopic and molecular docking studies. Bioorg. Med. Chem. 2016, 24, 1504-1512, doi:10.1016/j.bmc.2016.02.020.
18. Tang, J.; Yang, C.; Zhou, L.; Ma, F.; Liu, S.; Wei, S.; Zhou, J.; Zhou, Y. Studies on the binding behavior of prodigiosin with bovine hemoglobin by multi-spectroscopic techniques. Spectrochim. Acta. A Mol. Biomol. Spectrosc. 2012, 96, 461-467, doi:10.1016/j.saa.2012.05.059.
19. Darshan, N.; Manonmani, H.K. Prodigiosin and its potential applications. J. Food Sci. Technol. 2015, 52, 5393-5407, doi:10.1007/s13197-015-1740-4.
20. Soliev, A.B.; Hosokawa, K.; Enomoto, K. Bioactive pigments from marine bacteria: applications and physiological roles. Evid. Based Complement. Alternat. Med. 2011, 2011, 670349, doi:10.1155/2011/670349.
21. Marchal, E.; Smithen, D.A.; Uddin, M.I.; Robertson, A.W.; Jakeman, D.L.; Mollard, V.; Goodman, C.D.; MacDougall, K.S.; McFarland, S.A.; McFadden, G.I., et al. Synthesis and antimalarial activity of prodigiosenes. Org. Biomol. Chem. 2014, 12, 4132-4142, doi:10.1039/c3ob42548g.
22. Domrose, A.; Weihmann, R.; Thies, S.; Jaeger, K.E.; Drepper, T.; Loeschcke, A. Rapid generation of recombinant Pseudomonas putida secondary metabolite producers using yTREX. Synth. Syst. Biotechnol. 2017, 2, 310-319, doi:10.1016/j.synbio.2017.11.001.
23. You, Z.; Zhang, S.; Liu, X.; Wang, Y. Enhancement of prodigiosin synthetase (PigC) production from recombinant Escherichia coli through optimization of induction strategy and media. Prep. Biochem. Biotechnol. 2018, 48, 226-233, doi:10.1080/10826068.2017.1421965.
24. Liu, P.; Zhu, H.; Zheng, G.; Jiang, W.; Lu, Y. Metabolic engineering of Streptomyces coelicolor for enhanced prodigiosins (RED) production. Sci. China Life Sci. 2017, 60, 948-957, doi:10.1007/s11427-017-9117-x.
25. Domrose, A.; Klein, A.S.; Hage-Hulsmann, J.; Thies, S.; Svensson, V.; Classen, T.; Pietruszka, J.; Jaeger, K.E.; Drepper, T.; Loeschcke, A. Efficient recombinant production of prodigiosin in Pseudomonas putida. Front. Microbiol. 2015, 6, 972, doi:10.3389/fmicb.2015.00972.
26. Sumathi, C.; MohanaPriya, D.; Swarnalatha, S.; Dinesh, M.G.; Sekaran, G. Production of prodigiosin using tannery fleshing and evaluating its pharmacological effects. ScientificWorldJournal 2014, 2014, 290327, doi:10.1155/2014/290327.
27. Thomson, N.R.; Crow, M.A.; McGowan, S.J.; Cox, A.; Salmond, G.P. Biosynthesis of carbapenem antibiotic and prodigiosin pigment in Serratia is under quorum sensing control. Mol. Microbiol. 2000, 36, 539-556.
28. Nakashima, T.; Miyazaki, Y.; Matsuyama, Y.; Muraoka, W.; Yamaguchi, K.; Oda, T. Producing mechanism of an algicidal compound against red tide phytoplankton in a marine bacterium gamma-proteobacterium. Appl. Microbiol. Biotechnol. 2006, 73, 684-690, doi:10.1007/s00253-006-0507-2.
29. Hage-Hulsmann, J.; Grunberger, A.; Thies, S.; Santiago-Schubel, B.; Klein, A.S.; Pietruszka, J.; Binder, D.; Hilgers, F.; Domrose, A.; Drepper, T., et al. Natural biocide cocktails: Combinatorial antibiotic effects of prodigiosin and biosurfactants. PLoS One 2018, 13, e0200940, doi:10.1371/journal.pone.0200940.
30. Zhou, W.; Zeng, C.; Liu, R.; Chen, J.; Li, R.; Wang, X.; Bai, W.; Liu, X.; Xiang, T.; Zhang, L., et al. Antiviral activity and specific modes of action of bacterial prodigiosin against Bombyx mori nucleopolyhedrovirus in vitro. Appl. Microbiol. Biotechnol. 2016, 100, 3979-3988, doi:10.1007/s00253-015-7242-5.
31. Liang, T.W.; Chen, S.Y.; Chen, Y.C.; Chen, C.H.; Yen, Y.H.; Wang, S.L. Enhancement of prodigiosin production by Serratia marcescens TKU011 and its insecticidal activity relative to food colorants. J. Food Sci. 2013, 78, M1743-1751, doi:10.1111/1750-3841.12272.
32. Patil, C.D.; Patil, S.V.; Salunke, B.K.; Salunkhe, R.B. Prodigiosin produced by Serratia marcescens NMCC46 as a mosquito larvicidal agent against Aedes aegypti and Anopheles stephensi. Parasitol. Res. 2011, 109, 1179-1187, doi:10.1007/s00436-011-2365-9.
33. Suryawanshi, R.K.; Patil, C.D.; Borase, H.P.; Narkhede, C.P.; Salunke, B.K.; Patil, S.V. Mosquito larvicidal and pupaecidal potential of prodigiosin from Serratia marcescens and understanding its mechanism of action. Pestic. Biochem. Physiol. 2015, 123, 49-55, doi:10.1016/j.pestbp.2015.01.018.
34. Genes, C.; Baquero, E.; Echeverri, F.; Maya, J.D.; Triana, O. Mitochondrial dysfunction in Trypanosoma cruzi: the role of Serratia marcescens prodigiosin in the alternative treatment of Chagas disease. Parasit. Vectors 2011, 4, 66, doi:10.1186/1756-3305-4-66.
35. Colovic, M.B.; Krstic, D.Z.; Lazarevic-Pasti, T.D.; Bondzic, A.M.; Vasic, V.M. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr. Neuropharmacol. 2013, 11, 315-335, doi:10.2174/1570159X11311030006.
36. Linser, P.J.; Smith, K.E.; Seron, T.J.; Neira Oviedo, M. Carbonic anhydrases and anion transport in mosquito midgut pH regulation. J. Exp. Biol. 2009, 212, 1662-1671, doi:10.1242/jeb.028084.
37. Nepomuceno, D.B.; Santos, V.C.; Araujo, R.N.; Pereira, M.H.; Sant'Anna, M.R.; Moreira, L.A.; Gontijo, N.F. pH control in the midgut of Aedesaegypti under different nutritional conditions. J. Exp. Biol. 2017, 220, 3355-3362, doi:10.1242/jeb.158956.
38. Seganish, J.L.; Davis, J.T. Prodigiosin is a chloride carrier that can function as an anion exchanger. Chem. Commun. (Camb.) 2005, 10.1039/b511847f, 5781-5783, doi:10.1039/b511847f.
39. Tanigaki, K.; Sasaki, S.; Ohkuma, S. In bafilomycin A1-resistant cells, bafilomycin A1 raised lysosomal pH and both prodigiosins and concanamycin A inhibited growth through apoptosis. FEBS Lett. 2003, 537, 79-84.
40. Han, S.B.; Park, S.H.; Jeon, Y.J.; Kim, Y.K.; Kim, H.M.; Yang, K.H. Prodigiosin blocks T cell activation by inhibiting interleukin-2Ralpha expression and delays progression of autoimmune diabetes and collagen-induced arthritis. J. Pharmacol. Exp. Ther. 2001, 299, 415-425.
41. Han, S.B.; Lee, C.W.; Yoon, Y.D.; Kang, J.S.; Lee, K.H.; Yoon, W.K.; Kim, Y.K.; Lee, K.; Park, S.K.; Kim, H.M. Effective prevention of lethal acute graft-versus-host disease by combined immunosuppressive therapy with prodigiosin and cyclosporine A. Biochem. Pharmacol. 2005, 70, 1518-1526, doi:10.1016/j.bcp.2005.08.017.
42. Pandey, R.; Chander, R.; Sainis, K.B. Prodigiosins: a novel family of immunosuppressants with anti-cancer activity. Indian J. Biochem. Biophys. 2007, 44, 295-302.
43. Chang, C.C.; Wang, Y.H.; Chern, C.M.; Liou, K.T.; Hou, Y.C.; Peng, Y.T.; Shen, Y.C. Prodigiosin inhibits gp91(phox) and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia. Toxicol. Appl. Pharmacol. 2011, 257, 137-147, doi:10.1016/j.taap.2011.08.027.
44. Huh, J.E.; Yim, J.H.; Lee, H.K.; Moon, E.Y.; Rhee, D.K.; Pyo, S. Prodigiosin isolated from Hahella chejuensis suppresses lipopolysaccharide-induced NO production by inhibiting p38 MAPK, JNK and NF-kappaB activation in murine peritoneal macrophages. Int. Immunopharmacol. 2007, 7, 1825-1833, doi:10.1016/j.intimp.2007.09.002.
45. Krishna, P.S.; Vani, K.; Prasad, M.R.; Samatha, B.; Bindu, N.S.; Charya, M.A.; Reddy Shetty, P. In -silico molecular docking analysis of prodigiosin and cycloprodigiosin as COX-2 inhibitors. SpringerPlus 2013, 2, 172, doi:10.1186/2193-1801-2-172.
46. Rashidi, M.; Jebali, A. Liposomal prodigiosin and plasmid encoding serial GCA nucleotides reduce inflammation in microglial and astrocyte cells by ATM/ATR signaling. J. Neuroimmunol. 2019, 326, 75-78, doi:10.1016/j.jneuroim.2018.11.014.
47. Melvin, M.S.; Calcutt, M.W.; Noftle, R.E.; Manderville, R.A. Influence of the a-ring on the redox and nuclease properties of the prodigiosins: importance of the bipyrrole moiety in oxidative DNA cleavage. Chem. Res. Toxicol. 2002, 15, 742-748.
48. Cheng, S.Y.; Chen, N.F.; Kuo, H.M.; Yang, S.N.; Sung, C.S.; Sung, P.J.; Wen, Z.H.; Chen, W.F. Prodigiosin stimulates endoplasmic reticulum stress and induces autophagic cell death in glioblastoma cells. Apoptosis 2018, 23, 314-328, doi:10.1007/s10495-018-1456-9.
49. Pan, M.Y.; Shen, Y.C.; Lu, C.H.; Yang, S.Y.; Ho, T.F.; Peng, Y.T.; Chang, C.C. Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines. Toxicol. Appl. Pharmacol. 2012, 265, 325-334, doi:10.1016/j.taap.2012.08.034.
50. Cheng, M.F.; Lin, C.S.; Chen, Y.H.; Sung, P.J.; Lin, S.R.; Tong, Y.W.; Weng, C.F. Inhibitory Growth of Oral Squamous Cell Carcinoma Cancer via Bacterial Prodigiosin. Mar. Drugs 2017, 15, e224, doi:10.3390/md15070224.
51. Chiu, W.J.; Lin, S.R.; Chen, Y.H.; Tsai, M.J.; Leong, M.K.; Weng, C.F. Prodigiosin-Emerged PI3K/Beclin-1-Independent Pathway Elicits Autophagic Cell Death in Doxorubicin-Sensitive and -Resistant Lung Cancer. J. Clin. Med. 2018, 7, pii: E321, doi:10.3390/jcm7100321.
52. Abrahantes-Perez, M.C.; Reyes-Gonzalez, J.; Veliz Rios, G.; Bequet-Romero, M.; Gomez Riera, R.; Anais Gasmury, C.; Huerta, V.; Gonzalez, L.J.; Canino, C.; Garcia, J., et al. Cytotoxic proteins combined with prodigiosin obtained from Serratia marcescens have both broad and selective cytotoxic activity on tumor cells. J. Chemother. 2006, 18, 172-181, doi:10.1179/joc.2006.18.2.172.
53. Ho, T.F.; Peng, Y.T.; Chuang, S.M.; Lin, S.C.; Feng, B.L.; Lu, C.H.; Yu, W.J.; Chang, J.S.; Chang, C.C. Prodigiosin down-regulates survivin to facilitate paclitaxel sensitization in human breast carcinoma cell lines. Toxicol. Appl. Pharmacol. 2009, 235, 253-260, doi:10.1016/j.taap.2008.12.009.
54. Baumann, U. Serralysin and Related Enzymes. In Handbook of Proteolytic Enzymes, 2013; 10.1016/b978-0-12-382219-2.00180-0pp. 864-867.
55. National Cancer Institute. Oral Cavity, Pharyngeal, and Laryngeal Cancer Screening (PDQ(R)): Health Professional Version. In PDQ Cancer Information Summaries, Bethesda (MD), 2002.
56. Dhanuthai, K.; Rojanawatsirivej, S.; Thosaporn, W.; Kintarak, S.; Subarnbhesaj, A.; Darling, M.; Kryshtalskyj, E.; Chiang, C.P.; Shin, H.I.; Choi, S.Y., et al. Oral cancer: A multicenter study. Med. Oral Patol. Oral Cir. Bucal. 2018, 23, e23-e29, doi:10.4317/medoral.21999.
57. Montero, P.H.; Patel, S.G. Cancer of the Oral Cavity. Surg. Oncol. Clin. N. Am. 2015, 24, 491-508, doi:10.1016/j.soc.2015.03.006.
58. National Cancer Institute. Lip and Oral Cavity Cancer Treatment (Adult) (PDQ(R)): Health Professional Version. In PDQ Cancer Information Summaries, Bethesda (MD), 2002.
59. Shield, K.D.; Ferlay, J.; Jemal, A.; Sankaranarayanan, R.; Chaturvedi, A.K.; Bray, F.; Soerjomataram, I. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J. Clin. 2017, 67, 51-64, doi:10.3322/caac.21384.
60. Chen, S.W.; Zhang, Q.; Guo, Z.M.; Chen, W.K.; Liu, W.W.; Chen, Y.F.; Li, Q.L.; Liu, X.K.; Li, H.; Ou-Yang, D., et al. Trends in clinical features and survival of oral cavity cancer: fifty years of experience with 3,362 consecutive cases from a single institution. Cancer Manag. Res. 2018, 10, 4523-4535, doi:10.2147/CMAR.S171251.
61. Cheng, T.Y.; Cramb, S.M.; Baade, P.D.; Youlden, D.R.; Nwogu, C.; Reid, M.E. The International Epidemiology of Lung Cancer: Latest Trends, Disparities, and Tumor Characteristics. J. Thorac. Oncol. 2016, 11, 1653-1671, doi:10.1016/j.jtho.2016.05.021.
62. Gupta, N.; Gupta, R.; Acharya, A.K.; Patthi, B.; Goud, V.; Reddy, S.; Garg, A.; Singla, A. Changing Trends in oral cancer - a global scenario. Nepal J Epidemiol 2016, 6, 613-619, doi:10.3126/nje.v6i4.17255.
63. Kao, S.Y.; Lim, E. An overview of detection and screening of oral cancer in Taiwan. Chin. J. Dent. Res. 2015, 18, 7-12.
64. National Cancer Institute. Oral Cavity, Pharyngeal, and Laryngeal Cancer Prevention (PDQ(R)): Health Professional Version. In PDQ Cancer Information Summaries, Bethesda (MD), 2002.
65. Huang, S.H.; O'Sullivan, B. Oral cancer: Current role of radiotherapy and chemotherapy. Med. Oral Patol. Oral Cir. Bucal. 2013, 18, e233-240.
66. Liao, C.-T.; Lin, C.-Y.; Fan, K.-H.; Wang, H.-M. The Optimal Treatment Modality for Taiwan Oral Cavity Cancer Patients-Experience of a Medical Center. J. Cancer Res. Pract. 2015, 2, 103-116, doi:https://doi.org/10.6323/JCRP.2015.2.2.01.
67. Lo, W.L.; Kao, S.Y.; Chi, L.Y.; Wong, Y.K.; Chang, R.C. Outcomes of oral squamous cell carcinoma in Taiwan after surgical therapy: factors affecting survival. J. Oral Maxillofac. Surg. 2003, 61, 751-758, doi:https://doi.org/10.1016/S0278-2391(03)00149-6.
68. Wang, B.; Zhang, S.; Yue, K.; Wang, X.D. The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Chin. J. Cancer 2013, 32, 614-618, doi:10.5732/cjc.012.10219.
69. Yu, J.S.; Chen, Y.T.; Chiang, W.F.; Hsiao, Y.C.; Chu, L.J.; See, L.C.; Wu, C.S.; Tu, H.T.; Chen, H.W.; Chen, C.C., et al. Saliva protein biomarkers to detect oral squamous cell carcinoma in a high-risk population in Taiwan. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 11549-11554, doi:10.1073/pnas.1612368113.
70. McGowan, J.V.; Chung, R.; Maulik, A.; Piotrowska, I.; Walker, J.M.; Yellon, D.M. Anthracycline Chemotherapy and Cardiotoxicity. Cardiovasc. Drugs Ther. 2017, 31, 63-75, doi:10.1007/s10557-016-6711-0.
71. Motlagh, N.S.; Parvin, P.; Ghasemi, F.; Atyabi, F. Fluorescence properties of several chemotherapy drugs: doxorubicin, paclitaxel and bleomycin. Biomed. Opt. Express 2016, 7, 2400-2406, doi:10.1364/BOE.7.002400.
72. Alrushaid, S.; Sayre, C.L.; Yanez, J.A.; Forrest, M.L.; Senadheera, S.N.; Burczynski, F.J.; Lobenberg, R.; Davies, N.M. Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative. Pharmaceutics 2017, 9, doi:10.3390/pharmaceutics9030035.
73. Wen, H.; Jung, H.; Li, X. Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges. AAPS J 2015, 17, 1327-1340, doi:10.1208/s12248-015-9814-9.
74. Thorn, C.F.; Oshiro, C.; Marsh, S.; Hernandez-Boussard, T.; McLeod, H.; Klein, T.E.; Altman, R.B. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet. Genomics 2011, 21, 440-446, doi:10.1097/FPC.0b013e32833ffb56.
75. Mai, Y.; Yu, J.J.; Bartholdy, B.; Xu-Monette, Z.Y.; Knapp, E.E.; Yuan, F.; Chen, H.; Ding, B.B.; Yao, Z.; Das, B., et al. An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL. Blood 2016, 128, 2797-2807, doi:10.1182/blood-2016-03-705814.
76. Johnson-Arbor, K.; Dubey, R. Doxorubicin. In StatPearls, Treasure Island (FL), 2018.
77. Johansen, P.B. Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse. Cancer Chemother. Pharmacol. 1981, 5, 267-270.
78. Woodman, R.J.; Cysyk, R.L.; Kline, I.; Gang, M.; Venditti, J.M. Enhancement of the effectiveness of daunorubicin (NSC-82151) or adriamycin (NSC-123127) against early mouse L1210 leukemia with ICRF-159 (NSC-129943). Cancer Chemother. Rep. 1975, 59, 689-695.
79. Fetterly, G.J.; Aras, U.; Lal, D.; Murphy, M.; Meholick, P.D.; Wang, E.S. Development of a preclinical PK/PD model to assess antitumor response of a sequential aflibercept and doxorubicin-dosing strategy in acute myeloid leukemia. AAPS J 2013, 15, 662-673, doi:10.1208/s12248-013-9480-8.
80. Gustafson, D.L.; Rastatter, J.C.; Colombo, T.; Long, M.E. Doxorubicin pharmacokinetics: Macromolecule binding, metabolism, and excretion in the context of a physiologic model. J. Pharm. Sci. 2002, 91, 1488-1501, doi:10.1002/jps.10161.
81. Krischke, M.; Hempel, G.; Voller, S.; Andre, N.; D'Incalci, M.; Bisogno, G.; Kopcke, W.; Borowski, M.; Herold, R.; Boddy, A.V., et al. Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a "European Pediatric Oncology Off-patents Medicines Consortium" trial. Cancer Chemother. Pharmacol. 2016, 78, 1175-1184, doi:10.1007/s00280-016-3174-8.
82. Broxterman, H.J.; Gotink, K.J.; Verheul, H.M. Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib. Drug Resist. Updat. 2009, 12, 114-126, doi:10.1016/j.drup.2009.07.001.
83. Bradley, G.; Juranka, P.F.; Ling, V. Mechanism of multidrug resistance. Biochim. Biophys. Acta 1988, 948, 87-128, doi:10.1016/0304-419x(88)90006-6.
84. Liu, T.; Li, Z.; Zhang, Q.; De Amorim Bernstein, K.; Lozano-Calderon, S.; Choy, E.; Hornicek, F.J.; Duan, Z. Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug resistance. Oncotarget 2016, 7, 83502-83513, doi:10.18632/oncotarget.13148.
85. Komori, Y.; Arisawa, S.; Takai, M.; Yokoyama, K.; Honda, M.; Hayashi, K.; Ishigami, M.; Katano, Y.; Goto, H.; Ueyama, J., et al. Ursodeoxycholic acid inhibits overexpression of P-glycoprotein induced by doxorubicin in HepG2 cells. Eur. J. Pharmacol. 2014, 724, 161-167, doi:10.1016/j.ejphar.2013.12.023.
86. Waghray, D.; Zhang, Q. Inhibit or Evade Multidrug Resistance P-Glycoprotein in Cancer Treatment. J. Med. Chem. 2018, 61, 5108-5121, doi:10.1021/acs.jmedchem.7b01457.
87. Helleday, T. Chemotherapy-induced toxicity-a secondary effect caused by released DNA? Ann. Oncol. 2017, 28, 2054-2055, doi:10.1093/annonc/mdx349.
88. Grigorian, A.; O'Brien, C.B. Hepatotoxicity Secondary to Chemotherapy. J. Clin. Transl. Hepatol. 2014, 2, 95-102, doi:10.14218/JCTH.2014.00011.
89. Yu, Y.C.; Mao, Y.M.; Chen, C.W.; Chen, J.J.; Chen, J.; Cong, W.M.; Ding, Y.; Duan, Z.P.; Fu, Q.C.; Guo, X.Y., et al. CSH guidelines for the diagnosis and treatment of drug-induced liver injury. Hepatol. Int. 2017, 11, 221-241, doi:10.1007/s12072-017-9793-2.
90. King, P.D.; Perry, M.C. Hepatotoxicity of chemotherapy. Oncologist 2001, 6, 162-176.
91. Horie, S.; Oya, M.; Nangaku, M.; Yasuda, Y.; Komatsu, Y.; Yanagita, M.; Kitagawa, Y.; Kuwano, H.; Nishiyama, H.; Ishioka, C., et al. Guidelines for treatment of renal injury during cancer chemotherapy 2016. Clin. Exp. Nephrol. 2018, 22, 210-244, doi:10.1007/s10157-017-1448-z.
92. Perazella, M.A. Onco-nephrology: renal toxicities of chemotherapeutic agents. Clin. J. Am. Soc. Nephrol. 2012, 7, 1713-1721, doi:10.2215/CJN.02780312.
93. Renu, K.; Abilash, V.G.; Tirupathi Pichiah, P.B.; Arunachalam, S. Molecular mechanism of doxorubicin-induced cardiomyopathy - An update. Eur. J. Pharmacol. 2018, 818, 241-253, doi:10.1016/j.ejphar.2017.10.043.
94. Shafei, A.; El-Bakly, W.; Sobhy, A.; Wagdy, O.; Reda, A.; Aboelenin, O.; Marzouk, A.; El Habak, K.; Mostafa, R.; Ali, M.A., et al. A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer. Biomed. Pharmacother. 2017, 95, 1209-1218, doi:10.1016/j.biopha.2017.09.059.
95. Minderman, H.; Linssen, P.C.; Wessels, J.M.; Haanen, C. Doxorubicin toxicity in relation to the proliferative state of human hematopoietic cells. Exp. Hematol. 1991, 19, 110-114.
96. Martin, J.; Howard, S.C.; Pillai, A.; Vogel, P.; Naren, A.P.; Davis, S.; Ringwald-Smith, K.; Buddington, K.; Buddington, R.K. The weaned pig as a model for Doxorubicin-induced mucositis. Chemotherapy 2014, 60, 24-36, doi:10.1159/000365725.
97. Chatterjee, K.; Zhang, J.; Honbo, N.; Karliner, J.S. Doxorubicin cardiomyopathy. Cardiology 2010, 115, 155-162, doi:10.1159/000265166.
98. Volkova, M.; Russell, R., 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr. Cardiol. Rev. 2011, 7, 214-220.
99. Hayward, R.; Hydock, D.S. Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J. Am. Assoc. Lab. Anim. Sci. 2007, 46, 20-32.
100. Todorova, V.K.; Kaufmann, Y.J.C.; Kumarapeli, A.R.; Siegel, E.R.; Owen, A.; Aronson, J.H.; Makhoul, I.; Wei, J.; Theus, S.A.; Klimberg, S. Reducing doxorubicin cardiotoxicity in rats with mammary tumors by dantrolene. J. Clin. Oncol. 2017, 35, e12013-e12013, doi:10.1200/JCO.2017.35.15_suppl.e12013.
101. Mosaad, R.M.; Samir, A.; Ibrahim, H.M. Median lethal dose (LD50) and cytotoxicity of Adriamycin in female albino mice. J. Appl. Pharm. Sci. 2017, 7, 77-80, doi:10.7324/japs.2017.70312.
102. Baxter-Holland, M.; Dass, C.R. Doxorubicin, mesenchymal stem cell toxicity and antitumour activity: implications for clinical use. J. Pharm. Pharmacol. 2018, 70, 320-327, doi:10.1111/jphp.12869.
103. Pugazhendhi, A.; Edison, T.; Velmurugan, B.K.; Jacob, J.A.; Karuppusamy, I. Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life Sci. 2018, 200, 26-30, doi:10.1016/j.lfs.2018.03.023.
104. Asensio-Lopez, M.C.; Soler, F.; Pascual-Figal, D.; Fernandez-Belda, F.; Lax, A. Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes. PLoS One 2017, 12, e0172803, doi:10.1371/journal.pone.0172803.
105. Damiani, R.M.; Moura, D.J.; Viau, C.M.; Caceres, R.A.; Henriques, J.A.P.; Saffi, J. Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Arch. Toxicol. 2016, 90, 2063-2076, doi:10.1007/s00204-016-1759-y.
106. Kaminskas, L.M.; McLeod, V.M.; Kelly, B.D.; Sberna, G.; Boyd, B.J.; Williamson, M.; Owen, D.J.; Porter, C.J. A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems. Nanomedicine 2012, 8, 103-111, doi:10.1016/j.nano.2011.05.013.
107. Wang, Z.; He, Q.; Zhao, W.; Luo, J.; Gao, W. Tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates overcome doxorubicin resistance in cancer therapy. J. Control. Release 2017, 264, 66-75, doi:10.1016/j.jconrel.2017.08.017.
108. Tang, J.; Zhang, L.; Gao, H.; Liu, Y.; Zhang, Q.; Ran, R.; Zhang, Z.; He, Q. Co-delivery of doxorubicin and P-gp inhibitor by a reduction-sensitive liposome to overcome multidrug resistance, enhance anti-tumor efficiency and reduce toxicity. Drug Deliv. 2016, 23, 1130-1143, doi:10.3109/10717544.2014.990651.
109. Gupta, B.; Ramasamy, T.; Poudel, B.K.; Pathak, S.; Regmi, S.; Choi, J.Y.; Son, Y.; Thapa, R.K.; Jeong, J.H.; Kim, J.R., et al. Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors. ACS Appl. Mater. Interfaces 2017, 9, 9280-9290, doi:10.1021/acsami.6b09163.
110. Perillo, E.; Porto, S.; Falanga, A.; Zappavigna, S.; Stiuso, P.; Tirino, V.; Desiderio, V.; Papaccio, G.; Galdiero, M.; Giordano, A., et al. Liposome armed with herpes virus-derived gH625 peptide to overcome doxorubicin resistance in lung adenocarcinoma cell lines. Oncotarget 2016, 7, 4077-4092, doi:10.18632/oncotarget.6013.
111. Zhang, A.; Sun, H.; Wang, X. Potentiating therapeutic effects by enhancing synergism based on active constituents from traditional medicine. Phytother. Res. 2014, 28, 526-533, doi:10.1002/ptr.5032.
112. Xu, J.; Song, Z.; Guo, Q.; Li, J. Synergistic Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Microenvironment and Cancer Cells. Biomed. Res. Int. 2016, 2016, 1490738, doi:10.1155/2016/1490738.
113. Ramakrishnan, R.; Gabrilovich, D.I. Mechanism of synergistic effect of chemotherapy and immunotherapy of cancer. Cancer Immunol. Immunother. 2011, 60, 419-423, doi:10.1007/s00262-010-0930-1.
114. Fessele, K.L. Financial Toxicity: Management as an Adverse Effect of Cancer Treatment. Clin. J. Oncol. Nurs. 2017, 21, 762-764, doi:10.1188/17.CJON.762-764.
115. National Cancer Institute. Breast Cancer Treatment (PDQ(R)): Health Professional Version. In PDQ Cancer Information Summaries, Bethesda (MD), 2002.
116. Formica, V.; Zaniboni, A.; Loupakis, F.; Roselli, M. Noninferiority of three months versus six months of oxaliplatin-based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice? Int. J. Cancer 2018, 143, 2342-2350, doi:10.1002/ijc.31616.
117. Wezel, F.; Vallo, S.; Roghmann, F.; Young Academic Urologist Urothelial Carcinoma Group of the European Association of, U. Do we have biomarkers to predict response to neoadjuvant and adjuvant chemotherapy and immunotherapy in bladder cancer? Transl Androl Urol 2017, 6, 1067-1080, doi:10.21037/tau.2017.09.18.
118. Agarwala, V.; Choudhary, N.; Gupta, S. A Risk-benefit Assessment Approach to Selection of Adjuvant Chemotherapy in Elderly Patients with Early Breast Cancer: A Mini Review. Indian J. Med. Paediatr. Oncol. 2017, 38, 526-534, doi:10.4103/ijmpo.ijmpo_96_17.
119. Carvalho, C.; Glynne-Jones, R. Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer. Lancet Oncol. 2017, 18, e354-e363, doi:10.1016/S1470-2045(17)30346-7.
120. Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug resistance in cancer: an overview. Cancers (Basel) 2014, 6, 1769-1792, doi:10.3390/cancers6031769.
121. Amiri-Kordestani, L.; Basseville, A.; Kurdziel, K.; Fojo, A.T.; Bates, S.E. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist. Updat. 2012, 15, 50-61, doi:10.1016/j.drup.2012.02.002.
122. Turrini, E.; Ferruzzi, L.; Fimognari, C. Natural compounds to overcome cancer chemoresistance: toxicological and clinical issues. Expert Opin. Drug Metab. Toxicol. 2014, 10, 1677-1690, doi:10.1517/17425255.2014.972933.
123. National Cancer Institute. Non-Small Cell Lung Cancer Treatment (PDQ(R)): Health Professional Version. In PDQ Cancer Information Summaries, Bethesda (MD), 2002.
124. Wang, J.; Wei, Q.; Wang, X.; Tang, S.; Liu, H.; Zhang, F.; Mohammed, M.K.; Huang, J.; Guo, D.; Lu, M., et al. Transition to resistance: An unexpected role of the EMT in cancer chemoresistance. Gene Dis. 2016, 3, 3-6, doi:10.1016/j.gendis.2016.01.002.
125. Wade, C.; Kyprianou, N. Profiling Prostate Cancer Therapeutic Resistance. Int. J. Mol. Sci. 2018, 19, doi:10.3390/ijms19030904.
126. Huang, J.; Li, H.; Ren, G. Epithelial-mesenchymal transition and drug resistance in breast cancer (Review). Int. J. Oncol. 2015, 47, 840-848, doi:10.3892/ijo.2015.3084.
127. Fischer, K.R.; Durrans, A.; Lee, S.; Sheng, J.; Li, F.; Wong, S.T.C.; Choi, H.; El Rayes, T.; Ryu, S.; Troeger, J., et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015, 527, 472, doi:10.1038/nature15748
https://www.nature.com/articles/nature15748#supplementary-information.
128. Cheung-Ong, K.; Giaever, G.; Nislow, C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem. Biol. 2013, 20, 648-659, doi:10.1016/j.chembiol.2013.04.007.
129. Sakthivel, K.M.; Hariharan, S. Regulatory players of DNA damage repair mechanisms: Role in Cancer Chemoresistance. Biomed. Pharmacother. 2017, 93, 1238-1245, doi:10.1016/j.biopha.2017.07.035.
130. Nagel, Z.D.; Kitange, G.J.; Gupta, S.K.; Joughin, B.A.; Chaim, I.A.; Mazzucato, P.; Lauffenburger, D.A.; Sarkaria, J.N.; Samson, L.D. DNA Repair Capacity in Multiple Pathways Predicts Chemoresistance in Glioblastoma Multiforme. Cancer Res. 2017, 77, 198-206, doi:10.1158/0008-5472.CAN-16-1151.
131. Wang, L.; Mosel, A.J.; Oakley, G.G.; Peng, A. Deficient DNA damage signaling leads to chemoresistance to cisplatin in oral cancer. Mol. Cancer Ther. 2012, 11, 2401-2409, doi:10.1158/1535-7163.MCT-12-0448.
132. Hou, B.; Liu, R.; Qin, Z.; Luo, D.; Wang, Q.; Huang, S. Oral Chinese Herbal Medicine as an Adjuvant Treatment for Chemotherapy, or Radiotherapy, Induced Myelosuppression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Evid. Based Complement. Alternat. Med. 2017, 2017, 3432750, doi:10.1155/2017/3432750.
133. Hu, X.Q.; Sun, Y.; Lau, E.; Zhao, M.; Su, S.B. Advances in Synergistic Combinations of Chinese Herbal Medicine for the Treatment of Cancer. Curr. Cancer Drug Targets 2016, 16, 346-356.
134. Wang, Y.T.; Liu, H.S.; Su, C.L. Curcumin-enhanced chemosensitivity of FDA-approved platinum (II)-based anti-cancer drugs involves downregulation of nuclear endonuclease G and NF-kappaB as well as induction of apoptosis and G2/M arrest. Int. J. Food Sci. Nutr. 2014, 65, 368-374, doi:10.3109/09637486.2013.871694.
135. D'Aguanno, S.; D'Agnano, I.; De Canio, M.; Rossi, C.; Bernardini, S.; Federici, G.; Urbani, A. Shotgun proteomics and network analysis of neuroblastoma cell lines treated with curcumin. Mol. Biosyst. 2012, 8, 1068-1077, doi:10.1039/c2mb05498a.
136. Zhao, X.; Fang, Y.; Yang, Y.; Qin, Y.; Wu, P.; Wang, T.; Lai, H.; Meng, L.; Wang, D.; Zheng, Z., et al. Elaiophylin, a novel autophagy inhibitor, exerts antitumor activity as a single agent in ovarian cancer cells. Autophagy 2015, 11, 1849-1863, doi:10.1080/15548627.2015.1017185.
137. Ma, L.; Li, W.; Wang, R.; Nan, Y.; Wang, Q.; Liu, W.; Jin, F. Resveratrol enhanced anticancer effects of cisplatin on non-small cell lung cancer cell lines by inducing mitochondrial dysfunction and cell apoptosis. Int. J. Oncol. 2015, 47, 1460-1468, doi:10.3892/ijo.2015.3124.
138. Shih, W.L.; Yu, F.L.; Chang, C.D.; Liao, M.H.; Wu, H.Y.; Lin, P.Y. Suppression of AMF/PGI-mediated tumorigenic activities by ursolic acid in cultured hepatoma cells and in a mouse model. Mol. Carcinog. 2013, 52, 800-812, doi:10.1002/mc.21919.
139. Kang, Y.; Hu, W.; Bai, E.; Zheng, H.; Liu, Z.; Wu, J.; Jin, R.; Zhao, C.; Liang, G. Curcumin sensitizes human gastric cancer cells to 5-fluorouracil through inhibition of the NFkappaB survival-signaling pathway. Onco Targets Ther. 2016, 9, 7373-7384, doi:10.2147/OTT.S118272.
140. Shi, D.B.; Li, X.X.; Zheng, H.T.; Li, D.W.; Cai, G.X.; Peng, J.J.; Gu, W.L.; Guan, Z.Q.; Xu, Y.; Cai, S.J. Icariin-mediated inhibition of NF-kappaB activity enhances the in vitro and in vivo antitumour effect of 5-fluorouracil in colorectal cancer. Cell Biochem. Biophys. 2014, 69, 523-530, doi:10.1007/s12013-014-9827-5.
141. Zhang, H.; Ozaki, I.; Hamajima, H.; Iwane, S.; Takahashi, H.; Kawaguchi, Y.; Eguchi, Y.; Yamamoto, K.; Mizuta, T. Vitamin K2 augments 5-fluorouracil-induced growth inhibition of human hepatocellular carcinoma cells by inhibiting NF-kappaB activation. Oncol. Rep. 2011, 25, 159-166.
142. Hayeshi, R.; Masimirembwa, C.; Mukanganyama, S.; Ungell, A.L. The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux. Eur. J. Pharm. Sci. 2006, 29, 70-81, doi:10.1016/j.ejps.2006.05.009.
143. Chung, S.Y.; Sung, M.K.; Kim, N.H.; Jang, J.O.; Go, E.J.; Lee, H.J. Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch. Pharm. Res. 2005, 28, 823-828.
144. Osman, A.M.; Al-Malki, H.S.; Al-Harthi, S.E.; El-Hanafy, A.A.; Elashmaoui, H.M.; Elshal, M.F. Modulatory role of resveratrol on cytotoxic activity of cisplatin, sensitization and modification of cisplatin resistance in colorectal cancer cells. Mol. Med. Rep. 2015, 12, 1368-1374, doi:10.3892/mmr.2015.3513.
145. Wu, W.J.; Zhang, Y.; Zeng, Z.L.; Li, X.B.; Hu, K.S.; Luo, H.Y.; Yang, J.; Huang, P.; Xu, R.H. beta-phenylethyl isothiocyanate reverses platinum resistance by a GSH-dependent mechanism in cancer cells with epithelial-mesenchymal transition phenotype. Biochem. Pharmacol. 2013, 85, 486-496, doi:10.1016/j.bcp.2012.11.017.
146. Angelini, A.; Conti, P.; Ciofani, G.; Cuccurullo, F.; Di Ilio, C. Modulation of multidrug resistance P-glycoprotein activity by antiemetic compounds in human doxorubicin-resistant sarcoma cells (MES-SA/Dx-5): implications on cancer therapy. J. Biol. Regul. Homeost. Agents 2013, 27, 1029-1037.
147. Saleh, E.M.; El-awady, R.A.; Eissa, N.A.; Abdel-Rahman, W.M. Antagonism between curcumin and the topoisomerase II inhibitor etoposide: a study of DNA damage, cell cycle regulation and death pathways. Cancer Biol. Ther. 2012, 13, 1058-1071, doi:10.4161/cbt.21078.
148. Strippoli, S.; Lorusso, V.; Albano, A.; Guida, M. Herbal-drug interaction induced rhabdomyolysis in a liposarcoma patient receiving trabectedin. BMC Complement. Altern. Med. 2013, 13, 199, doi:10.1186/1472-6882-13-199.
149. Rejhova, A.; Opattova, A.; Cumova, A.; Sliva, D.; Vodicka, P. Natural compounds and combination therapy in colorectal cancer treatment. Eur. J. Med. Chem. 2018, 144, 582-594, doi:10.1016/j.ejmech.2017.12.039.
150. Hajra, S.; Basu, A.; Singha Roy, S.; Patra, A.R.; Bhattacharya, S. Attenuation of doxorubicin-induced cardiotoxicity and genotoxicity by an indole-based natural compound 3,3'-diindolylmethane (DIM) through activation of Nrf2/ARE signaling pathways and inhibiting apoptosis. Free Radic. Res. 2017, 51, 812-827, doi:10.1080/10715762.2017.1381694.
151. Hu, Q.; Zhang, D.D.; Wang, L.; Lou, H.; Ren, D. Eriodictyol-7-O-glucoside, a novel Nrf2 activator, confers protection against cisplatin-induced toxicity. Food Chem. Toxicol. 2012, 50, 1927-1932, doi:10.1016/j.fct.2012.03.059.
152. Adwas, A.A.; Elkhoely, A.A.; Kabel, A.M.; Abdel-Rahman, M.N.; Eissa, A.A. Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice. J. Infect. Chemother. 2016, 22, 36-43, doi:10.1016/j.jiac.2015.10.001.
153. Hosseinimehr, S.J.; Asadian, R.; Naghshvar, F.; Azizi, S.; Jafarinejad, M.; Noaparast, Z.; Abedi, S.M.; Hosseini, S.A. Protective effects of thymol against nephrotoxicity induced by cisplatin with using 99mTc-DMSA in mice. Ren. Fail. 2015, 37, 280-284, doi:10.3109/0886022X.2014.991998.
154. Mundhe, N.A.; Kumar, P.; Ahmed, S.; Jamdade, V.; Mundhe, S.; Lahkar, M. Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats. Int. Immunopharmacol. 2015, 28, 634-642, doi:10.1016/j.intimp.2015.07.016.
155. Roell, K.R.; Reif, D.M.; Motsinger-Reif, A.A. An Introduction to Terminology and Methodology of Chemical Synergy-Perspectives from Across Disciplines. Front. Pharmacol. 2017, 8, 158, doi:10.3389/fphar.2017.00158.
156. Chou, T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010, 70, 440-446, doi:10.1158/0008-5472.CAN-09-1947.
157. Wu, D.; Yotnda, P. Production and detection of reactive oxygen species (ROS) in cancers. J. Vis. Exp. 2011, 10.3791/3357, pii: 3357, doi:10.3791/3357.
158. Tsai, M.J.; Liao, J.F.; Lin, D.Y.; Huang, M.C.; Liou, D.Y.; Yang, H.C.; Lee, H.J.; Chen, Y.T.; Chi, C.W.; Huang, W.C., et al. Silymarin protects spinal cord and cortical cells against oxidative stress and lipopolysaccharide stimulation. Neurochem. Int. 2010, 57, 867-875, doi:10.1016/j.neuint.2010.09.005.
159. McGrail, D.J.; Khambhati, N.N.; Qi, M.X.; Patel, K.S.; Ravikumar, N.; Brandenburg, C.P.; Dawson, M.R. Alterations in ovarian cancer cell adhesion drive taxol resistance by increasing microtubule dynamics in a FAK-dependent manner. Sci. Rep. 2015, 5, 9529, doi:10.1038/srep09529.
160. Telford, W.G. Multiparametric Analysis of Apoptosis by Flow Cytometry. In Flow Cytometry Protocols, 2018; 10.1007/978-1-4939-7346-0_10pp. 167-202.
161. Klionsky, D.J.; Abdelmohsen, K.; Abe, A.; Abedin, M.J.; Abeliovich, H.; Acevedo Arozena, A.; Adachi, H.; Adams, C.M.; Adams, P.D.; Adeli, K., et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016, 12, 1-222, doi:10.1080/15548627.2015.1100356.
162. Ashoor, S.H.; Chu, F.S. Inhibition of muscle aldolase by penicillic acid and patulin in vitro. Food Cosmet. Toxicol. 1973, 11, 995-1000, doi:10.1016/0015-6264(73)90226-5.
163. Kang, H.J.; Song, H.Y.; Ahmed, M.A.; Guo, Y.; Zhang, M.; Chen, C.; Cristofanilli, M.; Horiuchi, D.; Vassilopoulos, A. NQO1 regulates mitotic progression and response to mitotic stress through modulating SIRT2 activity. Free Radic. Biol. Med. 2018, 126, 358-371, doi:10.1016/j.freeradbiomed.2018.08.009.
164. Kazama, K.; Okada, M.; Yamawaki, H. Adipocytokine, omentin inhibits doxorubicin-induced H9c2 cardiomyoblasts apoptosis through the inhibition of mitochondrial reactive oxygen species. Biochem. Biophys. Res. Commun. 2015, 457, 602-607, doi:10.1016/j.bbrc.2015.01.032.
165. Yi, C.; Tong, J.J.; Yu, L. Mitochondria: The hub of energy deprivation-induced autophagy. Autophagy 2018, 14, 1084-1085, doi:10.1080/15548627.2017.1382785.
166. Rashid, H.O.; Yadav, R.K.; Kim, H.R.; Chae, H.J. ER stress: Autophagy induction, inhibition and selection. Autophagy 2015, 11, 1956-1977, doi:10.1080/15548627.2015.1091141.
167. Filomeni, G.; De Zio, D.; Cecconi, F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015, 22, 377-388, doi:10.1038/cdd.2014.150.
168. Guerriero, E.; Sorice, A.; Capone, F.; Storti, G.; Colonna, G.; Ciliberto, G.; Costantini, S. Combining doxorubicin with a phenolic extract from flaxseed oil: Evaluation of the effect on two breast cancer cell lines. Int. J. Oncol. 2017, 50, 468-476, doi:10.3892/ijo.2017.3835.
169. Ma, Q. Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 2013, 53, 401-426, doi:10.1146/annurev-pharmtox-011112-140320.
170. Sutariya, B.; Saraf, M. alpha-asarone reduce proteinuria by restoring antioxidant enzymes activities and regulating necrosis factor kappaB signaling pathway in doxorubicin-induced nephrotic syndrome. Biomed. Pharmacother. 2018, 98, 318-324, doi:10.1016/j.biopha.2017.12.051.
171. Yang, Y.; Zhou, X.; Xu, M.; Piao, J.; Zhang, Y.; Lin, Z.; Chen, L. beta-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci. Rep. 2017, 7, 2681, doi:10.1038/s41598-017-02937-0.
172. Sanajou, D.; Nazari Soltan Ahmad, S.; Hosseini, V.; Kalantary-Charvadeh, A.; Marandi, Y.; Roshangar, L.; Bahrambeigi, S.; Mesgari-Abbasi, M. beta-Lapachone protects against doxorubicin-induced nephrotoxicity via NAD(+)/AMPK/NF-kB in mice. Naunyn Schmiedebergs Arch. Pharmacol. 2019, 392, 633-640, doi:10.1007/s00210-019-01619-0.
173. Sah, N.K.; Khan, Z.; Khan, G.J.; Bisen, P.S. Structural, functional and therapeutic biology of survivin. Cancer Lett. 2006, 244, 164-171, doi:10.1016/j.canlet.2006.03.007.
174. Wang, J.; Yuan, Z. Gambogic acid sensitizes ovarian cancer cells to doxorubicin through ROS-mediated apoptosis. Cell Biochem. Biophys. 2013, 67, 199-206, doi:10.1007/s12013-013-9534-7.
175. Sun, M.; Zhang, N.; Wang, X.; Cai, C.; Cun, J.; Li, Y.; Lv, S.; Yang, Q. Nitidine chloride induces apoptosis, cell cycle arrest, and synergistic cytotoxicity with doxorubicin in breast cancer cells. Tumour Biol. 2014, 35, 10201-10212, doi:10.1007/s13277-014-2327-9.
176. Al-Abbasi, F.A.; Alghamdi, E.A.; Baghdadi, M.A.; Alamoudi, A.J.; El-Halawany, A.M.; El-Bassossy, H.M.; Aseeri, A.H.; Al-Abd, A.M. Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity. Molecules 2016, 21, doi:10.3390/molecules21070886.
177. Wang, S.; Wang, L.; Shi, Z.; Zhong, Z.; Chen, M.; Wang, Y. Evodiamine synergizes with doxorubicin in the treatment of chemoresistant human breast cancer without inhibiting P-glycoprotein. PLoS One 2014, 9, e97512, doi:10.1371/journal.pone.0097512.
178. Poornima, P.; Kumar, V.B.; Weng, C.F.; Padma, V.V. Doxorubicin induced apoptosis was potentiated by neferine in human lung adenocarcima, A549 cells. Food Chem. Toxicol. 2014, 68, 87-98, doi:10.1016/j.fct.2014.03.008.
179. Liu, Q.; Sun, Y.; Zheng, J.M.; Yan, X.L.; Chen, H.M.; Chen, J.K.; Huang, H.Q. Formononetin sensitizes glioma cells to doxorubicin through preventing EMT via inhibition of histone deacetylase 5. Int. J. Clin. Exp. Pathol. 2015, 8, 6434-6441.
180. Yu, L.L.; Wu, J.G.; Dai, N.; Yu, H.G.; Si, J.M. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-kappaB transcription factor. Oncol. Rep. 2011, 26, 1197-1203, doi:10.3892/or.2011.1410.
181. Jabbour-Leung, N.A.; Chen, X.; Bui, T.; Jiang, Y.; Yang, D.; Vijayaraghavan, S.; McArthur, M.J.; Hunt, K.K.; Keyomarsi, K. Sequential Combination Therapy of CDK Inhibition and Doxorubicin Is Synthetically Lethal in p53-Mutant Triple-Negative Breast Cancer. Mol. Cancer Ther. 2016, 15, 593-607, doi:10.1158/1535-7163.MCT-15-0519.
182. Geretti, E.; Leonard, S.C.; Dumont, N.; Lee, H.; Zheng, J.; De Souza, R.; Gaddy, D.F.; Espelin, C.W.; Jaffray, D.A.; Moyo, V., et al. Cyclophosphamide-Mediated Tumor Priming for Enhanced Delivery and Antitumor Activity of HER2-Targeted Liposomal Doxorubicin (MM-302). Mol. Cancer Ther. 2015, 14, 2060-2071, doi:10.1158/1535-7163.MCT-15-0314.
183. Ihnat, M.A.; Nervi, A.M.; Anthony, S.P.; Kaltreider, R.C.; Warren, A.J.; Pesce, C.A.; Davis, S.A.; Lariviere, J.P.; Hamilton, J.W. Effects of mitomycin C and carboplatin pretreatment on multidrug resistance-associated P-glycoprotein expression and on subsequent suppression of tumor growth by doxorubicin and paclitaxel in human metastatic breast cancer xenografted nude mice. Oncol. Res. 1999, 11, 303-310.
184. Elahian, F.; Moghimi, B.; Dinmohammadi, F.; Ghamghami, M.; Hamidi, M.; Mirzaei, S.A. The anticancer agent prodigiosin is not a multidrug resistance protein substrate. DNA Cell Biol. 2013, 32, 90-97, doi:10.1089/dna.2012.1902.
185. Okabe, M.; Unno, M.; Harigae, H.; Kaku, M.; Okitsu, Y.; Sasaki, T.; Mizoi, T.; Shiiba, K.; Takanaga, H.; Terasaki, T., et al. Characterization of the organic cation transporter SLC22A16: a doxorubicin importer. Biochem. Biophys. Res. Commun. 2005, 333, 754-762, doi:10.1016/j.bbrc.2005.05.174.
186. Ota, K.; Ito, K.; Akahira, J.; Sato, N.; Onogawa, T.; Moriya, T.; Unno, M.; Abe, T.; Niikura, H.; Takano, T., et al. Expression of organic cation transporter SLC22A16 in human epithelial ovarian cancer: a possible role of the adriamycin importer. Int. J. Gynecol. Pathol. 2007, 26, 334-340, doi:10.1097/01.pgp.0000236951.33914.1b.
187. Kunii, E.; Oguri, T.; Kasai, D.; Ozasa, H.; Uemura, T.; Takakuwa, O.; Ohkubo, H.; Takemura, M.; Maeno, K.; Niimi, A. Organic cation transporter OCT6 mediates cisplatin uptake and resistance to cisplatin in lung cancer. Cancer Chemother. Pharmacol. 2015, 75, 985-991, doi:10.1007/s00280-015-2723-x.
188. Lee, W.K.; Thevenod, F. Oncogenic PITX2 facilitates tumor cell drug resistance by inverse regulation of hOCT3/SLC22A3 and ABC drug transporters in colon and kidney cancers. Cancer Lett. 2019, 449, 237-251, doi:10.1016/j.canlet.2019.01.044.
189. Durmus, S.; Naik, J.; Buil, L.; Wagenaar, E.; van Tellingen, O.; Schinkel, A.H. In vivo disposition of doxorubicin is affected by mouse Oatp1a/1b and human OATP1A/1B transporters. Int. J. Cancer 2014, 135, 1700-1710, doi:10.1002/ijc.28797.
190. Lee, H.H.; Leake, B.F.; Kim, R.B.; Ho, R.H. Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance. Mol. Pharmacol. 2017, 91, 14-24, doi:10.1124/mol.116.105544.
191. Lu, X.; Chan, T.; Cheng, Z.; Shams, T.; Zhu, L.; Murray, M.; Zhou, F. The 5′-AMP-Activated Protein Kinase Regulates the Function and Expression of Human Organic Anion Transporting Polypeptide 1A2. Mol. Pharmacol. 2018, 94, 1412-1420, doi:10.1124/mol.118.113423.
192. Uhlen, M.; Fagerberg, L.; Hallstrom, B.M.; Lindskog, C.; Oksvold, P.; Mardinoglu, A.; Sivertsson, A.; Kampf, C.; Sjostedt, E.; Asplund, A., et al. Proteomics. Tissue-based map of the human proteome. Science 2015, 347, 1260419, doi:10.1126/science.1260419.
193. Lin, S.R.; Fu, Y.S.; Tsai, M.J.; Cheng, H.; Weng, C.F. Natural Compounds from Herbs that can Potentially Execute as Autophagy Inducers for Cancer Therapy. Int. J. Mol. Sci. 2017, 18, e1412, doi:10.3390/ijms18071412.
194. Anding, A.L.; Baehrecke, E.H. Autophagy in Cell Life and Cell Death. Curr. Top. Dev. Biol. 2015, 114, 67-91, doi:10.1016/bs.ctdb.2015.07.012.
195. Parzych, K.R.; Klionsky, D.J. An overview of autophagy: morphology, mechanism, and regulation. Antioxid. Redox Signal. 2014, 20, 460-473, doi:10.1089/ars.2013.5371.
196. Lee, W.S.; Yoo, W.H.; Chae, H.J. ER Stress and Autophagy. Curr. Mol. Med. 2015, 15, 735-745.
197. Zhang, Y.; Qu, P.; Ma, X.; Qiao, F.; Ma, Y.; Qing, S.; Zhang, Y.; Wang, Y.; Cui, W. Tauroursodeoxycholic acid (TUDCA) alleviates endoplasmic reticulum stress of nuclear donor cells under serum starvation. PLoS One 2018, 13, e0196785, doi:10.1371/journal.pone.0196785.
198. Liu, X.; Chhipa, R.R.; Nakano, I.; Dasgupta, B. The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent. Mol. Cancer Ther. 2014, 13, 596-605, doi:10.1158/1535-7163.MCT-13-0579.
199. Tacar, O.; Sriamornsak, P.; Dass, C.R. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J. Pharm. Pharmacol. 2013, 65, 157-170, doi:10.1111/j.2042-7158.2012.01567.x.
200. Dirks-Naylor, A.J. The role of autophagy in doxorubicin-induced cardiotoxicity. Life Sci. 2013, 93, 913-916.
201. Zhao, D.; Yuan, H.; Yi, F.; Meng, C.; Zhu, Q. Autophagy prevents doxorubicininduced apoptosis in osteosarcoma. Mol. Med. Rep. 2014, 9, 1975-1981, doi:10.3892/mmr.2014.2055.
202. Gomes, L.R.; Vessoni, A.T.; Menck, C.F. Three-dimensional microenvironment confers enhanced sensitivity to doxorubicin by reducing p53-dependent induction of autophagy. Oncogene 2015, 34, 5329-5340, doi:10.1038/onc.2014.461.
203. Zilinyi, R.; Czompa, A.; Czegledi, A.; Gajtko, A.; Pituk, D.; Lekli, I.; Tosaki, A. The Cardioprotective Effect of Metformin in Doxorubicin-Induced Cardiotoxicity: The Role of Autophagy. Molecules 2018, 23, doi:10.3390/molecules23051184.
204. Bando, M.; Hasegawa, M.; Tsuboi, Y.; Miyake, Y.; Shiina, M.; Ito, M.; Handa, H.; Nagai, K.; Kataoka, T. The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking self-processing of caspase-8 in death-inducing signaling complex. J. Biol. Chem. 2003, 278, 5786-5793, doi:10.1074/jbc.M204178200.
205. Park, E.J.; Min, K.J.; Choi, K.S.; Kwon, T.K. Dicoumarol sensitizes renal cell carcinoma Caki cells to TRAIL-induced apoptosis through down-regulation of Bcl-2, Mcl-1 and c-FLIP in a NQO1-independent manner. Exp. Cell Res. 2014, 323, 144-154, doi:10.1016/j.yexcr.2014.01.009.
206. Matsui, Y.; Watanabe, J.; Ding, S.; Nishizawa, K.; Kajita, Y.; Ichioka, K.; Saito, R.; Kobayashi, T.; Ogawa, O.; Nishiyama, H. Dicoumarol enhances doxorubicin-induced cytotoxicity in p53 wild-type urothelial cancer cells through p38 activation. BJU Int. 2010, 105, 558-564, doi:10.1111/j.1464-410X.2009.08732.x.
207. Madari, H.; Panda, D.; Wilson, L.; Jacobs, R.S. Dicoumarol: a unique microtubule stabilizing natural product that is synergistic with Taxol. Cancer Res. 2003, 63, 1214-1220.
208. Ito, Y.; Mitani, T.; Harada, N.; Isayama, A.; Tanimori, S.; Takenaka, S.; Nakano, Y.; Inui, H.; Yamaji, R. Identification of carbonyl reductase 1 as a resveratrol-binding protein by affinity chromatography using 4'-amino-3,5-dihydroxy-trans-stilbene. J. Nutr. Sci. Vitaminol. (Tokyo) 2013, 59, 358-364.
209. Piska, K.; Koczurkiewicz, P.; Wnuk, D.; Karnas, E.; Bucki, A.; Wojcik-Pszczola, K.; Jamrozik, M.; Michalik, M.; Kolaczkowski, M.; Pekala, E. Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells - The involvement of carbonyl reductase 1 inhibition. Chem. Biol. Interact. 2019, 300, 40-48, doi:10.1016/j.cbi.2019.01.003.
210. Bousova, I.; Skalova, L.; Soucek, P.; Matouskova, P. The modulation of carbonyl reductase 1 by polyphenols. Drug Metab. Rev. 2015, 47, 520-533, doi:10.3109/03602532.2015.1089885.
211. Srijiwangsa, P.; Ponnikorn, S.; Na-Bangchang, K. Effect of beta-Eudesmol on NQO1 suppression-enhanced sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. BMC Pharmacol Toxicol 2018, 19, 32, doi:10.1186/s40360-018-0223-4.
212. Zhong, Y.; Zhang, F.; Sun, Z.; Zhou, W.; Li, Z.Y.; You, Q.D.; Guo, Q.L.; Hu, R. Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response. Mol. Carcinog. 2013, 52, 824-834, doi:10.1002/mc.21921.
213. Zhou, F.; Hao, G.; Zhang, J.; Zheng, Y.; Wu, X.; Hao, K.; Niu, F.; Luo, D.; Sun, Y.; Wu, L., et al. Protective effect of 23-hydroxybetulinic acid on doxorubicin-induced cardiotoxicity: a correlation with the inhibition of carbonyl reductase-mediated metabolism. Br. J. Pharmacol. 2015, 172, 5690-5703, doi:10.1111/bph.12995.
214. Han, X.; Pan, J.; Ren, D.; Cheng, Y.; Fan, P.; Lou, H. Naringenin-7-O-glucoside protects against doxorubicin-induced toxicity in H9c2 cardiomyocytes by induction of endogenous antioxidant enzymes. Food Chem. Toxicol. 2008, 46, 3140-3146, doi:10.1016/j.fct.2008.06.086.
215. Zhao, L.; Tao, X.; Qi, Y.; Xu, L.; Yin, L.; Peng, J. Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress. Redox Biol 2018, 16, 189-198, doi:10.1016/j.redox.2018.02.026.
216. Zeekpudsa, P.; Kukongviriyapan, V.; Senggunprai, L.; Sripa, B.; Prawan, A. Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents. J. Exp. Clin. Cancer Res. 2014, 33, 11, doi:10.1186/1756-9966-33-11.
217. Yagata, H.; Kajiura, Y.; Yamauchi, H. Current strategy for triple-negative breast cancer: appropriate combination of surgery, radiation, and chemotherapy. Breast Cancer 2011, 18, 165-173, doi:10.1007/s12282-011-0254-9.
218. Li, D.; Liu, J.; Wang, X.; Kong, D.; Du, W.; Li, H.; Hse, C.Y.; Shupe, T.; Zhou, D.; Zhao, K. Biological Potential and Mechanism of Prodigiosin from Serratia marcescens Subsp. lawsoniana in Human Choriocarcinoma and Prostate Cancer Cell Lines. Int. J. Mol. Sci. 2018, 19, doi:10.3390/ijms19113465.
219. Kim, D.; Lee, J.S.; Park, Y.K.; Kim, J.F.; Jeong, H.; Oh, T.K.; Kim, B.S.; Lee, C.H. Biosynthesis of antibiotic prodiginines in the marine bacterium Hahella chejuensis KCTC 2396. J. Appl. Microbiol. 2007, 102, 937-944, doi:10.1111/j.1365-2672.2006.03172.x.
220. O'Brien, K.; Perron, G.G.; Jude, B.A. Draft Genome Sequence of a Red-Pigmented Janthinobacterium sp. Native to the Hudson Valley Watershed. Genome Announc. 2018, 6, doi:10.1128/genomeA.01429-17.
221. Song, M.J.; Bae, J.; Lee, D.S.; Kim, C.H.; Kim, J.S.; Kim, S.W.; Hong, S.I. Purification and characterization of prodigiosin produced by integrated bioreactor from Serratia sp. KH-95. J. Biosci. Bioeng. 2006, 101, 157-161, doi:10.1263/jbb.101.157.
222. Su, C.; Liu, Y.; Sun, Y.; Li, Z. Complete genome sequence of Serratia sp. YD25 (KCTC 42987) presenting strong antagonistic activities to various pathogenic fungi and bacteria. J. Biotechnol. 2017, 245, 9-13, doi:10.1016/j.jbiotec.2017.01.011.
223. Woodhams, D.C.; LaBumbard, B.C.; Barnhart, K.L.; Becker, M.H.; Bletz, M.C.; Escobar, L.A.; Flechas, S.V.; Forman, M.E.; Iannetta, A.A.; Joyce, M.D., et al. Prodigiosin, Violacein, and Volatile Organic Compounds Produced by Widespread Cutaneous Bacteria of Amphibians Can Inhibit Two Batrachochytrium Fungal Pathogens. Microb. Ecol. 2018, 75, 1049-1062, doi:10.1007/s00248-017-1095-7.
224. Li, P.; Kwok, A.H.; Jiang, J.; Ran, T.; Xu, D.; Wang, W.; Leung, F.C. Comparative genome analyses of Serratia marcescens FS14 reveals its high antagonistic potential. PLoS One 2015, 10, e0123061, doi:10.1371/journal.pone.0123061.
225. Berg, G. Diversity of antifungal and plant-associated Serratia plymuthica strains. J. Appl. Microbiol. 2000, 88, 952-960.
226. Miao, L.; Wang, X.; Jiang, W.; Yang, S.; Zhou, H.; Zhai, Y.; Zhou, X.; Dong, K. Optimization of the culture condition for an antitumor bacterium Serratia proteamacula 657 and identification of the active compounds. World J. Microbiol. Biotechnol. 2013, 29, 855-863, doi:10.1007/s11274-012-1240-x.
227. Siva, R.; Subha, K.; Bhakta, D.; Ghosh, A.R.; Babu, S. Characterization and enhanced production of prodigiosin from the spoiled coconut. Appl. Biochem. Biotechnol. 2012, 166, 187-196, doi:10.1007/s12010-011-9415-8.
228. Su, C.; Xiang, Z.; Liu, Y.; Zhao, X.; Sun, Y.; Li, Z.; Li, L.; Chang, F.; Chen, T.; Wen, X., et al. Analysis of the genomic sequences and metabolites of Serratia surfactantfaciens sp. nov. YD25(T) that simultaneously produces prodigiosin and serrawettin W2. BMC Genomics 2016, 17, 865, doi:10.1186/s12864-016-3171-7.
229. El-Bondkly, A.M.; El-Gendy, M.M.; Bassyouni, R.H. Overproduction and biological activity of prodigiosin-like pigments from recombinant fusant of endophytic marine Streptomyces species. Antonie Van Leeuwenhoek 2012, 102, 719-734, doi:10.1007/s10482-012-9772-5.
230. Lucena, T.; Arahal, D.R.; Ruvira, M.A.; Navarro-Torre, S.; Mesa, J.; Pajuelo, E.; Rodriguez-Llorente, I.D.; Rodrigo-Torres, L.; Pinar, M.J.; Pujalte, M.J. Vibrio palustris sp. nov. and Vibrio spartinae sp. nov., two novel members of the Gazogenes clade, isolated from salt-marsh plants (Arthrocnemum macrostachyum and Spartina maritima). Int. J. Syst. Evol. Microbiol. 2017, 67, 3506-3512, doi:10.1099/ijsem.0.002155.
231. Lee, J.S.; Kim, Y.S.; Park, S.; Kim, J.; Kang, S.J.; Lee, M.H.; Ryu, S.; Choi, J.M.; Oh, T.K.; Yoon, J.H. Exceptional production of both prodigiosin and cycloprodigiosin as major metabolic constituents by a novel marine bacterium, Zooshikella rubidus S1-1. Appl. Environ. Microbiol. 2011, 77, 4967-4973, doi:10.1128/AEM.01986-10.
232. Kim, S.J.; Lee, H.K.; Lee, Y.K.; Yim, J.H. Mutant selection of Hahella chejuensis KCTC 2396 and statistical optimization of medium components for prodigiosin yield-up. J. Microbiol. 2008, 46, 183-188, doi:10.1007/s12275-008-0037-y.
233. Kim, S.J.; Lee, H.K.; Yim, J.H. Statistical optimization of medium components for the production of prodigiosin by Hahella chejuensis KCTC 2396. J. Microbiol. Biotechnol. 2008, 18, 1903-1907.
234. Monson, R.E.; Tashiro, Y.; Salmond, G.P. Overproduction of individual gas vesicle proteins perturbs flotation, antibiotic production and cell division in the enterobacterium Serratia sp. ATCC 39006. Microbiology 2016, 162, 1595-1607, doi:10.1099/mic.0.000347.
235. Umamaheswari, B.; Priya, K.; Rajaram, R. Bioremediation of synthetic fatliquors under microaerobic condition. Water Sci. Technol. 2017, 75, 1118-1127, doi:10.2166/wst.2016.603.
236. Rastegari, B.; Karbalaei-Heidari, H.R. Sulfate as a pivotal factor in regulation of Serratia sp. strain S2B pigment biosynthesis. Res. Microbiol. 2016, 167, 638-646, doi:10.1016/j.resmic.2016.05.005.
237. Chen, W.C.; Tsai, M.J.; Soo, P.C.; Wang, L.F.; Tsai, S.L.; Chang, Y.K.; Wei, Y.H. Construction and co-cultivation of two mutant strains harboring key precursor genes to produce prodigiosin. J. Biosci. Bioeng. 2018, 126, 783-789, doi:10.1016/j.jbiosc.2018.06.010.
238. Haddix, P.L.; Shanks, R.M.Q. Prodigiosin pigment of Serratia marcescens is associated with increased biomass production. Arch. Microbiol. 2018, 200, 989-999, doi:10.1007/s00203-018-1508-0.
239. Suryawanshi, R.K.; Patil, C.D.; Borase, H.P.; Salunke, B.K.; Patil, S.V. Studies on production and biological potential of prodigiosin by Serratia marcescens. Appl. Biochem. Biotechnol. 2014, 173, 1209-1221, doi:10.1007/s12010-014-0921-3.
240. Haddix, P.L.; Jones, S.; Patel, P.; Burnham, S.; Knights, K.; Powell, J.N.; LaForm, A. Kinetic analysis of growth rate, ATP, and pigmentation suggests an energy-spilling function for the pigment prodigiosin of Serratia marcescens. J. Bacteriol. 2008, 190, 7453-7463, doi:10.1128/JB.00909-08.
241. Giri, A.V.; Anandkumar, N.; Muthukumaran, G.; Pennathur, G. A novel medium for the enhanced cell growth and production of prodigiosin from Serratia marcescens isolated from soil. BMC Microbiol. 2004, 4, 11, doi:10.1186/1471-2180-4-11.
242. Gutierrez-Roman, M.I.; Holguin-Melendez, F.; Bello-Mendoza, R.; Guillen-Navarro, K.; Dunn, M.F.; Huerta-Palacios, G. Production of prodigiosin and chitinases by tropical Serratia marcescens strains with potential to control plant pathogens. World J. Microbiol. Biotechnol. 2012, 28, 145-153, doi:10.1007/s11274-011-0803-6.
243. Elkenawy, N.M.; Yassin, A.S.; Elhifnawy, H.N.; Amin, M.A. Optimization of prodigiosin production by Serratia marcescens using crude glycerol and enhancing production using gamma radiation. Biotechnol. Rep. (Amst.) 2017, 14, 47-53, doi:10.1016/j.btre.2017.04.001.
244. Kurbanoglu, E.B.; Ozdal, M.; Ozdal, O.G.; Algur, O.F. Enhanced production of prodigiosin by Serratia marcescens MO-1 using ram horn peptone. Braz. J. Microbiol. 2015, 46, 631-637, doi:10.1590/S1517-838246246220131143.
245. Wei, Y.H.; Chen, W.C. Enhanced production of prodigiosin-like pigment from Serratia marcescens SMdeltaR by medium improvement and oil-supplementation strategies. J. Biosci. Bioeng. 2005, 99, 616-622, doi:10.1263/jbb.99.616.
246. de Araujo, H.W.; Fukushima, K.; Takaki, G.M. Prodigiosin production by Serratia marcescens UCP 1549 using renewable-resources as a low cost substrate. Molecules 2010, 15, 6931-6940, doi:10.3390/molecules15106931.
247. Gondil, V.S.; Asif, M.; Bhalla, T.C. Optimization of physicochemical parameters influencing the production of prodigiosin from Serratia nematodiphila RL2 and exploring its antibacterial activity. 3 Biotech 2017, 7, 338, doi:10.1007/s13205-017-0979-z.
248. Ndlovu, T.M.; Ward, A.C.; Glassey, J.; Eskildsen, J.; Akay, G. Bioprocess intensification of antibiotic production by Streptomyces coelicolor A3(2) in micro-porous culture. Mater. Sci. Eng. C Mater. Biol. Appl. 2015, 49, 799-806, doi:10.1016/j.msec.2015.01.052.
249. Morgenstern, A.; Paetz, C.; Behrend, A.; Spiteller, D. Divalent transition-metal-ion stress induces prodigiosin biosynthesis in Streptomyces coelicolor M145: formation of coeligiosins. Chemistry (Easton) 2015, 21, 6027-6032, doi:10.1002/chem.201405733.
250. Gallardo, K.; Candia, J.E.; Remonsellez, F.; Escudero, L.V.; Demergasso, C.S. The Ecological Coherence of Temperature and Salinity Tolerance Interaction and Pigmentation in a Non-marine Vibrio Isolated from Salar de Atacama. Front. Microbiol. 2016, 7, 1943, doi:10.3389/fmicb.2016.01943.
251. Darshan, N.; Manonmani, H.K. Prodigiosin inhibits motility and activates bacterial cell death revealing molecular biomarkers of programmed cell death. AMB Express 2016, 6, 50, doi:10.1186/s13568-016-0222-z.
252. Danevcic, T.; Boric Vezjak, M.; Tabor, M.; Zorec, M.; Stopar, D. Prodigiosin Induces Autolysins in Actively Grown Bacillus subtilis Cells. Front. Microbiol. 2016, 7, 27, doi:10.3389/fmicb.2016.00027.
253. Suryawanshi, R.K.; Patil, C.D.; Koli, S.H.; Hallsworth, J.E.; Patil, S.V. Antimicrobial activity of prodigiosin is attributable to plasma-membrane damage. Nat. Prod. Res. 2017, 31, 572-577, doi:10.1080/14786419.2016.1195380.
254. Lapenda, J.C.; Silva, P.A.; Vicalvi, M.C.; Sena, K.X.; Nascimento, S.C. Antimicrobial activity of prodigiosin isolated from Serratia marcescens UFPEDA 398. World J. Microbiol. Biotechnol. 2015, 31, 399-406, doi:10.1007/s11274-014-1793-y.
255. Danevcic, T.; Boric Vezjak, M.; Zorec, M.; Stopar, D. Prodigiosin - A Multifaceted Escherichia coli Antimicrobial Agent. PLoS One 2016, 11, e0162412, doi:10.1371/journal.pone.0162412.
256. Kimyon, O.; Das, T.; Ibugo, A.I.; Kutty, S.K.; Ho, K.K.; Tebben, J.; Kumar, N.; Manefield, M. Serratia Secondary Metabolite Prodigiosin Inhibits Pseudomonas aeruginosa Biofilm Development by Producing Reactive Oxygen Species that Damage Biological Molecules. Front. Microbiol. 2016, 7, 972, doi:10.3389/fmicb.2016.00972.
257. Yang, K.; Chen, Q.; Zhang, D.; Zhang, H.; Lei, X.; Chen, Z.; Li, Y.; Hong, Y.; Ma, X.; Zheng, W., et al. The algicidal mechanism of prodigiosin from Hahella sp. KA22 against Microcystis aeruginosa. Sci. Rep. 2017, 7, 7750, doi:10.1038/s41598-017-08132-5.
258. Arivizhivendhan, K.V.; Mahesh, M.; Boopathy, R.; Patchaimurugan, K.; Maharaja, P.; Swarnalatha, S.; Regina Mary, R.; Sekaran, G. Synthesis of Surface-Modified Iron Oxides for the Solvent-Free Recovery of Bacterial Bioactive Compound Prodigiosin and Its Algicidal Activity. J. Phys. Chem. B 2016, 120, 9685-9696, doi:10.1021/acs.jpcb.6b03926.
259. Duzhak, A.B.; Panfilova, Z.I.; Duzhak, T.G.; Vasyunina, E.A.; Shternshis, M.V. Role of prodigiosin and chitinases in antagonistic activity of the bacterium Serratia marcescens against the fungus Didymella applanata. Biochemistry (Mosc.) 2012, 77, 910-916, doi:10.1134/S0006297912080123.
260. Kim, D.; Kim, J.F.; Yim, J.H.; Kwon, S.K.; Lee, C.H.; Lee, H.K. Red to red - the marine bacterium Hahella chejuensis and its product prodigiosin for mitigation of harmful algal blooms. J. Microbiol. Biotechnol. 2008, 18, 1621-1629.
261. Zhang, H.; Wang, H.; Zheng, W.; Yao, Z.; Peng, Y.; Zhang, S.; Hu, Z.; Tao, Z.; Zheng, T. Toxic Effects of Prodigiosin Secreted by Hahella sp. KA22 on Harmful Alga Phaeocystis globosa. Front. Microbiol. 2017, 8, 999, doi:10.3389/fmicb.2017.00999.
262. Zhang, H.; Peng, Y.; Zhang, S.; Cai, G.; Li, Y.; Yang, X.; Yang, K.; Chen, Z.; Zhang, J.; Wang, H., et al. Algicidal Effects of Prodigiosin on the Harmful Algae Phaeocystis globosa. Front. Microbiol. 2016, 7, 602, doi:10.3389/fmicb.2016.00602.
263. Campas, C.; Dalmau, M.; Montaner, B.; Barragan, M.; Bellosillo, B.; Colomer, D.; Pons, G.; Perez-Tomas, R.; Gil, J. Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukemia. Leukemia 2003, 17, 746-750, doi:10.1038/sj.leu.2402860.
264. Sam, M.R.; Ghoreishi, S. Prodigiosin produced by Serratia marcescens inhibits expression of MMP-9 and survivin and promotes caspase-3 activation with induction of apoptosis in acute lymphoblastic leukaemia cells. J. Appl. Microbiol. 2018, 125, 1017-1029, doi:10.1111/jam.13949.
265. Montaner, B.; Navarro, S.; Pique, M.; Vilaseca, M.; Martinell, M.; Giralt, E.; Gil, J.; Perez-Tomas, R. Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines. Br. J. Pharmacol. 2000, 131, 585-593, doi:10.1038/sj.bjp.0703614.
266. Lins, J.C.; ME, D.E.M.; SC, D.O.N.; Adam, M.L. Differential genomic damage in different tumor lines induced by prodigiosin. Anticancer Res. 2015, 35, 3325-3332.
267. Soliev, A.B.; Hosokawa, K.; Enomoto, K. Effects of prodigiosin family compounds from Pseudoalteromonas sp. 1020R on the activities of protein phosphatases and protein kinases. J. Enzyme Inhib. Med. Chem. 2015, 30, 533-538, doi:10.3109/14756366.2014.951347.
268. Montaner, B.; Perez-Tomas, R. Prodigiosin induces caspase-9 and caspase-8 activation and cytochrome C release in Jurkat T cells. Ann. N. Y. Acad. Sci. 2002, 973, 246-249.
269. Perez-Tomas, R.; Montaner, B. Effects of the proapoptotic drug prodigiosin on cell cycle-related proteins in Jurkat T cells. Histol. Histopathol. 2003, 18, 379-385, doi:10.14670/HH-18.379.
270. Montaner, B.; Perez-Tomas, R. The cytotoxic prodigiosin induces phosphorylation of p38-MAPK but not of SAPK/JNK. Toxicol. Lett. 2002, 129, 93-98.
271. Ramoneda, B.M.; Perez-Tomas, R. Activation of protein kinase C for protection of cells against apoptosis induced by the immunosuppressor prodigiosin. Biochem. Pharmacol. 2002, 63, 463-469.
272. Montaner, B.; Castillo-Avila, W.; Martinell, M.; Ollinger, R.; Aymami, J.; Giralt, E.; Perez-Tomas, R. DNA interaction and dual topoisomerase I and II inhibition properties of the anti-tumor drug prodigiosin. Toxicol. Sci. 2005, 85, 870-879, doi:10.1093/toxsci/kfi149.
273. Sam, M.R.; Pourpak, R.S. Regulation of p53 and survivin by prodigiosin compound derived from Serratia marcescens contribute to caspase-3-dependent apoptosis in acute lymphoblastic leukemia cells. Hum. Exp. Toxicol. 2018, 37, 608-617, doi:10.1177/0960327117718052.
274. Wang, Y.; Nakajima, A.; Hosokawa, K.; Soliev, A.B.; Osaka, I.; Arakawa, R.; Enomoto, K. Cytotoxic prodigiosin family pigments from Pseudoalteromonas sp. 1020R isolated from the Pacific coast of Japan. Biosci. Biotechnol. Biochem. 2012, 76, 1229-1232, doi:10.1271/bbb.110984.
275. Francisco, R.; Perez-Tomas, R.; Gimenez-Bonafe, P.; Soto-Cerrato, V.; Gimenez-Xavier, P.; Ambrosio, S. Mechanisms of prodigiosin cytotoxicity in human neuroblastoma cell lines. Eur. J. Pharmacol. 2007, 572, 111-119, doi:10.1016/j.ejphar.2007.06.054.
276. Soto-Cerrato, V.; Vinals, F.; Lambert, J.R.; Kelly, J.A.; Perez-Tomas, R. Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3beta activity in human breast cancer cells. Mol. Cancer Ther. 2007, 6, 362-369, doi:10.1158/1535-7163.MCT-06-0266.
277. Lu, C.H.; Lin, S.C.; Yang, S.Y.; Pan, M.Y.; Lin, Y.W.; Hsu, C.Y.; Wei, Y.H.; Chang, J.S.; Chang, C.C. Prodigiosin-induced cytotoxicity involves RAD51 down-regulation through the JNK and p38 MAPK pathways in human breast carcinoma cell lines. Toxicol. Lett. 2012, 212, 83-89, doi:10.1016/j.toxlet.2012.05.002.
278. Soto-Cerrato, V.; Vinals, F.; Lambert, J.R.; Perez-Tomas, R. The anticancer agent prodigiosin induces p21WAF1/CIP1 expression via transforming growth factor-beta receptor pathway. Biochem. Pharmacol. 2007, 74, 1340-1349, doi:10.1016/j.bcp.2007.07.016.
279. Monge, M.; Vilaseca, M.; Soto-Cerrato, V.; Montaner, B.; Giralt, E.; Perez-Tomas, R. Proteomic analysis of prodigiosin-induced apoptosis in a breast cancer mitoxantrone-resistant (MCF-7 MR) cell line. Invest. New Drugs 2007, 25, 21-29, doi:10.1007/s10637-006-7774-8.
280. Wang, Z.; Li, B.; Zhou, L.; Yu, S.; Su, Z.; Song, J.; Sun, Q.; Sha, O.; Wang, X.; Jiang, W., et al. Prodigiosin inhibits Wnt/beta-catenin signaling and exerts anticancer activity in breast cancer cells. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 13150-13155, doi:10.1073/pnas.1616336113.
281. Dalili, D.; Fouladdel, S.; Rastkari, N.; Samadi, N.; Ahmadkhaniha, R.; Ardavan, A.; Azizi, E. Prodigiosin, the red pigment of Serratia marcescens, shows cytotoxic effects and apoptosis induction in HT-29 and T47D cancer cell lines. Nat. Prod. Res. 2012, 26, 2078-2083, doi:10.1080/14786419.2011.622276.
282. Prabhu, V.V.; Hong, B.; Allen, J.E.; Zhang, S.; Lulla, A.R.; Dicker, D.T.; El-Deiry, W.S. Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated DeltaNp73 Inhibition and p73 Activation. Cancer Res. 2016, 76, 1989-1999, doi:10.1158/0008-5472.CAN-14-2430.
283. Hong, B.; Prabhu, V.V.; Zhang, S.; van den Heuvel, A.P.; Dicker, D.T.; Kopelovich, L.; El-Deiry, W.S. Prodigiosin rescues deficient p53 signaling and antitumor effects via upregulating p73 and disrupting its interaction with mutant p53. Cancer Res. 2014, 74, 1153-1165, doi:10.1158/0008-5472.CAN-13-0955.
284. Montaner, B.; Perez-Tomas, R. Prodigiosin-induced apoptosis in human colon cancer cells. Life Sci. 2001, 68, 2025-2036.
285. Castillo-Avila, W.; Abal, M.; Robine, S.; Perez-Tomas, R. Non-apoptotic concentrations of prodigiosin (H+/Cl- symporter) inhibit the acidification of lysosomes and induce cell cycle blockage in colon cancer cells. Life Sci. 2005, 78, 121-127, doi:10.1016/j.lfs.2005.04.059.
286. Hassankhani, R.; Sam, M.R.; Esmaeilou, M.; Ahangar, P. Prodigiosin isolated from cell wall of Serratia marcescens alters expression of apoptosis-related genes and increases apoptosis in colorectal cancer cells. Med. Oncol. 2015, 32, 366, doi:10.1007/s12032-014-0366-0.
287. Yenkejeh, R.A.; Sam, M.R.; Esmaeillou, M. Targeting survivin with prodigiosin isolated from cell wall of Serratia marcescens induces apoptosis in hepatocellular carcinoma cells. Hum. Exp. Toxicol. 2017, 36, 402-411, doi:10.1177/0960327116651122.
288. Zhang, J.; Shen, Y.; Liu, J.; Wei, D. Antimetastatic effect of prodigiosin through inhibition of tumor invasion. Biochem. Pharmacol. 2005, 69, 407-414, doi:10.1016/j.bcp.2004.08.037.
289. Hsieh, H.Y.; Shieh, J.J.; Chen, C.J.; Pan, M.Y.; Yang, S.Y.; Lin, S.C.; Chang, J.S.; Lee, A.Y.; Chang, C.C. Prodigiosin down-regulates SKP2 to induce p27(KIP1) stabilization and antiproliferation in human lung adenocarcinoma cells. Br. J. Pharmacol. 2012, 166, 2095-2108, doi:10.1111/j.1476-5381.2012.01921.x.
290. Llagostera, E.; Soto-Cerrato, V.; Montaner, B.; Perez-Tomas, R. Prodigiosin induces apoptosis by acting on mitochondria in human lung cancer cells. Ann. N. Y. Acad. Sci. 2003, 1010, 178-181.
291. Llagostera, E.; Soto-Cerrato, V.; Joshi, R.; Montaner, B.; Gimenez-Bonafe, P.; Perez-Tomas, R. High cytotoxic sensitivity of the human small cell lung doxorubicin-resistant carcinoma (GLC4/ADR) cell line to prodigiosin through apoptosis activation. Anticancer Drugs 2005, 16, 393-399.
292. Liu, Y.; Zhou, H.; Ma, X.; Lin, C.; Lu, L.; Liu, D.; Ma, D.; Gao, X.; Qian, X.Y. Prodigiosin Inhibits Proliferation, Migration, and Invasion of Nasopharyngeal Cancer Cells. Cell. Physiol. Biochem. 2018, 48, 1556-1562, doi:10.1159/000492278.
293. Espona-Fiedler, M.; Soto-Cerrato, V.; Hosseini, A.; Lizcano, J.M.; Guallar, V.; Quesada, R.; Gao, T.; Perez-Tomas, R. Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: prodigiosin vs. obatoclax. Biochem. Pharmacol. 2012, 83, 489-496, doi:10.1016/j.bcp.2011.11.027.
294. Diaz-Ruiz, C.; Montaner, B.; Perez-Tomas, R. Prodigiosin induces cell death and morphological changes indicative of apoptosis in gastric cancer cell line HGT-1. Histol. Histopathol. 2001, 16, 415-421, doi:10.14670/HH-16.415.
295. Lopes, J.A.; Jorge, S. The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review. Clin Kidney J 2013, 6, 8-14, doi:10.1093/ckj/sfs160.
296. Guo, Y.; An, H.; Feng, L.; Liu, Q.; Wang, S.; Zhang, T. Sinapine as an active compound for inhibiting the proliferation of Caco-2 cells via downregulation of P-glycoprotein. Food Chem. Toxicol. 2014, 67, 187-192, doi:10.1016/j.fct.2014.02.035.
297. Wang, A.; Wang, W.; Chen, Y.; Ma, F.; Wei, X.; Bi, Y. Deguelin induces PUMA-mediated apoptosis and promotes sensitivity of lung cancer cells (LCCs) to doxorubicin (Dox). Mol. Cell. Biochem. 2018, 442, 177-186, doi:10.1007/s11010-017-3202-y.
298. Wang, Z.D.; Wang, R.Z.; Xia, Y.Z.; Kong, L.Y.; Yang, L. Reversal of multidrug resistance by icaritin in doxorubicin-resistant human osteosarcoma cells. Chin. J. Nat. Med. 2018, 16, 20-28, doi:10.1016/S1875-5364(18)30026-8.
299. Catanzaro, D.; Gabbia, D.; Cocetta, V.; Biagi, M.; Ragazzi, E.; Montopoli, M.; Carrara, M. Silybin counteracts doxorubicin resistance by inhibiting GLUT1 expression. Fitoterapia 2018, 124, 42-48, doi:10.1016/j.fitote.2017.10.007.
300. He, Y.; Khan, M.; Yang, J.; Yao, M.; Yu, S.; Gao, H. Proscillaridin A induces apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in prostate cancer cells. Int. J. Med. Sci. 2018, 15, 832-839, doi:10.7150/ijms.23270.
301. Zhang, Z.L.; Jiang, Q.C.; Wang, S.R. Schisandrin A reverses doxorubicin-resistant human breast cancer cell line by the inhibition of P65 and Stat3 phosphorylation. Breast Cancer 2018, 25, 233-242, doi:10.1007/s12282-017-0821-9.
302. Sun, J.; Yeung, C.A.; Co, N.N.; Tsang, T.Y.; Yau, E.; Luo, K.; Wu, P.; Wa, J.C.; Fung, K.P.; Kwok, T.T., et al. Clitocine reversal of P-glycoprotein associated multi-drug resistance through down-regulation of transcription factor NF-kappaB in R-HepG2 cell line. PLoS One 2012, 7, e40720, doi:10.1371/journal.pone.0040720.
303. Pastorek, M.; Simko, V.; Takacova, M.; Barathova, M.; Bartosova, M.; Hunakova, L.; Sedlakova, O.; Hudecova, S.; Krizanova, O.; Dequiedt, F., et al. Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy. Int. J. Oncol. 2015, 47, 51-60, doi:10.3892/ijo.2015.2987.
304. Sandholt, I.S.; Olsen, B.B.; Guerra, B.; Issinger, O.G. Resorufin: a lead for a new protein kinase CK2 inhibitor. Anticancer Drugs 2009, 20, 238-248, doi:10.1097/CAD.0b013e328326472e.
305. Wu, L.; Liu, X.; Cao, K.X.; Ni, Z.H.; Li, W.D.; Chen, Z.P. Synergistic antitumor effects of rhein and doxorubicin in hepatocellular carcinoma cells. J. Cell. Biochem. 2018, 10.1002/jcb.27514, doi:10.1002/jcb.27514.
306. Wu, L.; Cao, K.; Ni, Z.; Wang, S.; Li, W.; Liu, X.; Chen, Z. Rhein reverses doxorubicin resistance in SMMC-7721 liver cancer cells by inhibiting energy metabolism and inducing mitochondrial permeability transition pore opening. Biofactors 2019, 45, 85-96, doi:10.1002/biof.1462.
307. Ni, F.; Huang, X.; Chen, Z.; Qian, W.; Tong, X. Shikonin exerts antitumor activity in Burkitt's lymphoma by inhibiting C-MYC and PI3K/AKT/mTOR pathway and acts synergistically with doxorubicin. Sci. Rep. 2018, 8, 3317, doi:10.1038/s41598-018-21570-z.
308. Jin, X.; Wei, Y.; Liu, Y.; Lu, X.; Ding, F.; Wang, J.; Yang, S. Resveratrol promotes sensitization to Doxorubicin by inhibiting epithelial-mesenchymal transition and modulating SIRT1/beta-catenin signaling pathway in breast cancer. Cancer Med. 2019, 8, 1246-1257, doi:10.1002/cam4.1993.
309. Tormo, J.R.; Royo, I.; Gallardo, T.; Zafra-Polo, M.C.; Hernandez, P.; Cortes, D.; Pelaez, F. In vitro antitumor structure-activity relationships of threo/trans/threo mono-tetrahydrofuranic acetogenins: correlations with their inhibition of mitochondrial complex I. Oncol. Res. 2003, 14, 147-154.
310. Sheng, W.; Mao, H.; Wang, C.; Yang, N.; Zhang, Z.; Han, J. Dehydrocostus Lactone Enhances Chemotherapeutic Potential of Doxorubicin in Lung Cancer by Inducing Cell Death and Limiting Metastasis. Med. Sci. Monit. 2018, 24, 7850-7861, doi:10.12659/MSM.911410.
311. Santos, G.C.; Almeida, M.R.; Antunes, L.; Bianchi, M. Effect of bixin on DNA damage and cell death induced by doxorubicin in HL60 cell line. Hum. Exp. Toxicol. 2016, 35, 1319-1327, doi:10.1177/0960327116630352.
312. Namazi Sarvestani, N.; Sepehri, H.; Delphi, L.; Moridi Farimani, M. Eupatorin and Salvigenin Potentiate Doxorubicin-Induced Apoptosis and Cell Cycle Arrest in HT-29 and SW948 Human Colon Cancer Cells. Asian Pac. J. Cancer Prev. 2018, 19, 131-139, doi:10.22034/APJCP.2018.19.1.131.
313. Di, Y.; De Silva, F.; Krol, E.S.; Alcorn, J. Flaxseed Lignans Enhance the Cytotoxicity of Chemotherapeutic Agents against Breast Cancer Cell Lines MDA-MB-231 and SKBR3. Nutr. Cancer 2018, 70, 306-315, doi:10.1080/01635581.2018.1421677.
314. Richards, C.E.; Vellanki, S.H.; Smith, Y.E.; Hopkins, A.M. Diterpenoid natural compound C4 (Crassin) exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species. Cell. Oncol. (Dordr.) 2018, 41, 35-46, doi:10.1007/s13402-017-0357-1.
315. Pham, M.Q.; Iscache, A.L.; Pham, Q.L.; Gairin, J.E. Cytotoxic, apoptotic, and sensitization properties of ent-kaurane-type diterpenoids from Croton tonkinensis Gagnep on human liver cancer HepG2 and Hep3b cell lines. Fundam. Clin. Pharmacol. 2016, 30, 137-146, doi:10.1111/fcp.12176.
316. Hanusova, V.; Caltova, K.; Svobodova, H.; Ambroz, M.; Skarka, A.; Murinova, N.; Kralova, V.; Tomsik, P.; Skalova, L. The effects of beta-caryophyllene oxide and trans-nerolidol on the efficacy of doxorubicin in breast cancer cells and breast tumor-bearing mice. Biomed. Pharmacother. 2017, 95, 828-836, doi:10.1016/j.biopha.2017.09.008.
317. Rethy, B.; Hohmann, J.; Minorics, R.; Varga, A.; Ocsovszki, I.; Molnar, J.; Juhasz, K.; Falkay, G.; Zupko, I. Antitumour properties of acridone alkaloids on a murine lymphoma cell line. Anticancer Res. 2008, 28, 2737-2743.
318. Fu, L.W.; Deng, Z.A.; Pan, Q.C.; Fan, W. Screening and discovery of novel MDR modifiers from naturally occurring bisbenzylisoquinoline alkaloids. Anticancer Res. 2001, 21, 2273-2280.
319. Xu, D.; Tian, W.; Shen, H. P-gp upregulation may be blocked by natural curcuminoids, a novel class of chemoresistance-preventing agent. Mol. Med. Rep. 2013, 7, 115-121, doi:10.3892/mmr.2012.1106.
320. Nabekura, T.; Yamaki, T.; Ueno, K.; Kitagawa, S. Inhibition of P-glycoprotein and multidrug resistance protein 1 by dietary phytochemicals. Cancer Chemother. Pharmacol. 2008, 62, 867-873, doi:10.1007/s00280-007-0676-4.
321. Hintzpeter, J.; Seliger, J.M.; Hofman, J.; Martin, H.J.; Wsol, V.; Maser, E. Inhibition of human anthracycline reductases by emodin - A possible remedy for anthracycline resistance. Toxicol. Appl. Pharmacol. 2016, 293, 21-29, doi:10.1016/j.taap.2016.01.003.
322. Sun, H.; Huang, M.; Yao, N.; Hu, J.; Li, Y.; Chen, L.; Hu, N.; Ye, W.; Chi-Shing Tai, W.; Zhang, D., et al. The cycloartane triterpenoid ADCX impairs autophagic degradation through Akt overactivation and promotes apoptotic cell death in multidrug-resistant HepG2/ADM cells. Biochem. Pharmacol. 2017, 146, 87-100, doi:10.1016/j.bcp.2017.10.012.
323. Villar, V.H.; Vogler, O.; Barcelo, F.; Gomez-Florit, M.; Martinez-Serra, J.; Obrador-Hevia, A.; Martin-Broto, J.; Ruiz-Gutierrez, V.; Alemany, R. Oleanolic and maslinic acid sensitize soft tissue sarcoma cells to doxorubicin by inhibiting the multidrug resistance protein MRP-1, but not P-glycoprotein. J. Nutr. Biochem. 2014, 25, 429-438, doi:10.1016/j.jnutbio.2013.12.003.
324. Zong, L.; Cheng, G.; Liu, S.; Pi, Z.; Liu, Z.; Song, F. Reversal of multidrug resistance in breast cancer cells by a combination of ursolic acid with doxorubicin. J. Pharm. Biomed. Anal. 2019, 165, 268-275, doi:10.1016/j.jpba.2018.11.057.
325. Hahnvajanawong, C.; Wattanawongdon, W.; Chomvarin, C.; Anantachoke, N.; Kanthawong, S.; Sripa, B.; Reutrakul, V. Synergistic effects of isomorellin and forbesione with doxorubicin on apoptosis induction in human cholangiocarcinoma cell lines. Cancer Cell Int. 2014, 14, 68, doi:10.1186/1475-2867-14-68.
326. Louisa, M.; Soediro, T.M.; Suyatna, F.D. In vitro modulation of P-glycoprotein, MRP-1 and BCRP expression by mangiferin in doxorubicin-treated MCF-7 cells. Asian Pac. J. Cancer Prev. 2014, 15, 1639-1642.
327. Shabalala, S.C.; Dludla, P.V.; Muller, C.J.F.; Nxele, X.; Kappo, A.P.; Louw, J.; Johnson, R. Aspalathin ameliorates doxorubicin-induced oxidative stress in H9c2 cardiomyoblasts. Toxicol. In Vitro 2019, 55, 134-139, doi:10.1016/j.tiv.2018.12.012.
328. Huang, P.C.; Kuo, W.W.; Shen, C.Y.; Chen, Y.F.; Lin, Y.M.; Ho, T.J.; Padma, V.V.; Lo, J.F.; Huang, C.Y.; Huang, C.Y. Anthocyanin Attenuates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-alpha/beta and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway. Int. J. Mol. Sci. 2016, 17, 1588, doi:10.3390/ijms17091588.
329. Xu, Z.M.; Li, C.B.; Liu, Q.L.; Li, P.; Yang, H. Ginsenoside Rg1 Prevents Doxorubicin-Induced Cardiotoxicity through the Inhibition of Autophagy and Endoplasmic Reticulum Stress in Mice. Int. J. Mol. Sci. 2018, 19, doi:10.3390/ijms19113658.
330. Yu, J.; Gao, H.; Wu, C.; Xu, Q.M.; Lu, J.J.; Chen, X. Diethyl Blechnic, a Novel Natural Product Isolated from Salvia miltiorrhiza Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2. Int. J. Mol. Sci. 2018, 19, doi:10.3390/ijms19061809.
331. Sunitha, M.C.; Dhanyakrishnan, R.; PrakashKumar, B.; Nevin, K.G. p-Coumaric acid mediated protection of H9c2 cells from Doxorubicin-induced cardiotoxicity: Involvement of augmented Nrf2 and autophagy. Biomed. Pharmacother. 2018, 102, 823-832, doi:10.1016/j.biopha.2018.03.089.
332. Zhang, Q.L.; Yang, J.J.; Zhang, H.S. Carvedilol (CAR) combined with carnosic acid (CAA) attenuates doxorubicin-induced cardiotoxicity by suppressing excessive oxidative stress, inflammation, apoptosis and autophagy. Biomed. Pharmacother. 2019, 109, 71-83, doi:10.1016/j.biopha.2018.07.037.
333. Mu, H.; Liu, H.; Zhang, J.; Huang, J.; Zhu, C.; Lu, Y.; Shi, Y.; Wang, Y. Ursolic acid prevents doxorubicin-induced cardiac toxicity in mice through eNOS activation and inhibition of eNOS uncoupling. J. Cell. Mol. Med. 2019, 23, 2174-2183, doi:10.1111/jcmm.14130.