Carboplatin and oxaliplatin in sequenced combination with bortezomib in ovarian tumour models

Journal of Ovarian Research

Fazlul Huq²  Jun Q Yu²  Charles Chan³  Philip Beale¹  Zaynab Al-Eisawi² 

[1] Sydney Cancer Centre, Concord Hospital, Sydney, NSW 2139, Australia;Cumberland Campus, The University of Sydney, Lidcombe, Sydney, NSW 2141, Australia;Anatomical Pathology Department, Concord Hospital, Sydney, NSW 2139, Australia

关键词: Proteasomal degradation;    Oxaliplatin;    Resistance;    Drug combination;    Copper transporter 1;    Cisplatin;    Carboplatin;    Bortezomib;   

Others  :  805070
DOI  :  10.1186/1757-2215-6-78

 received in 2013-05-24, accepted in 2013-10-29,  发布年份 2013

【 摘 要 】

Background

Ovarian cancer remains an on-going challenge mainly due to the development of drug resistance and also because the cancer is likely to have metastasized at the time of diagnosis. Currently, chemotherapy based on platinum drugs such as cisplatin is the primary treatment for the disease. Copper transporter 1 is involved in the transport of cisplatin into the cell, but is also down-regulated by the drug. Bortezomib, a proteasome inhibitor, has been reported to block this platinum-induced down-regulation of CTR1, so that in the presence of bortezomib, the cellular uptake of platinum drugs may be increased. Increased platinum accumulation may result in increased platinum − DNA binding so that the platinum drug in combination with bortezomib may produce enhanced cell kill.

Methods

In this study the efficacy of the sequential combinations of carboplatin, oxaliplatin and a trans-platinum compound coded as CH1 with BORT on the human ovarian A2780, A2780^cisR, A2780^ZD0473R and SKOV-3 cancer cell lines was evaluated. The levels of cellular platinum accumulation and platinum-DNA binding were determined following the treatment with these combinations. In order to investigate the effect of the combinations of the formation of ROS, the total and oxidized glutathione levels were also determined.

Results

Prevention of copper transporter 1 degradation by bortezomib is found to enhance the cellular accumulation of platinum, the level of Platinum − DNA binding and increases oxidative stress especially in the resistant cell lines.

Conclusions

The results suggest that the prevention of CTR1 degradation by bortezomib may be playing a major role in increasing the cellular uptake of platinum drugs and platinum-DNA binding level. Furthermore, the generation of oxidative stress appears to be a major contributor to the enhanced cell kill.

【 授权许可】

   
2013 Al-Eisawi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Wang D, Lippard SJ: Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 2005, 4:307-320.
• [2]Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003, 22:7265-7279.
• [3]Samimi G, Safaei R, Katano K, Holzer AK, Rochdi M, Tomioka M, Goodman M, Howell SB: Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res 2004, 10:4661-4669.
• [4]Muggia FM, Los G: Platinum resistance: laboratory findings and clinical implications. Stem Cells 1993, 11:182-193.
• [5]Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM: The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol 2008, 48:495-535.
• [6]Safaei R: Role of copper transporters in the uptake and efflux of platinum containing drugs. Cancer Lett 2005, 234:34-39.
• [7]Beretta GL, Gatti L, Tinelli S, Corna E, Colangelo D, Zunino F, Perego P: Cellular pharmacology of cisplatin in relation to the expression of human copper transporter CTR1 in different pairs of cisplatin-sensitive and -resistant cells. Biochem Pharmacol 2004, 68:283-291.
• [8]Larson CA, Blair BG, Safaei R, Howell SB: The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs. Mol Pharmacol 2009, 75:324-330.
• [9]Holzer AK, Manorek GH, Howell SB: Contribution of the major copper influx transporter CTR1 to the cellular accumulation of cisplatin, carboplatin, and oxaliplatin. Mol Pharmacol 2006, 70:1390-1394.
• [10]Burger H, Zoumaro-Djayoon A, Boersma AWM, Helleman J, Berns E, Mathijssen RHJ, Loos WJ, Wiemer EAC: Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2). Br J Pharmacol 2010, 159:898-908.
• [11]Ishida S, Lee J, Thiele DJ, Herskowitz I: Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci U S A 2002, 99:14298-14302.
• [12]Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, Kuo MT: Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther 2004, 3:1543-1549.
• [13]Holzer AK, Samimi G, Katano K, Naerdemann W, Lin X, Safaei R, Howell SB: The copper influx transporter human copper transport protein 1 regulates the uptake of cisplatin in human ovarian carcinoma cells. Mol Pharmacol 2004, 66:817-823.
• [14]Safaei R, Otani S, Larson BJ, Rasmussen ML, Howell SB: Transport of cisplatin by the copper efflux transporter ATP7B. Mol Pharmacol 2008, 73:461-468.
• [15]Holzer AK, Howell SB: The internalization and degradation of human copper transporter following cisplatin exposure. Cancer Res 2006, 66:10944-10952.
• [16]Jandial DD, Farshchi-Heydari S, Larson CA, Elliott GI, Wrasidlo WJ, Howell SB: Enhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1. Clin Cancer Res 2009, 15:553-560.
• [17]Guo Y, Smith K, Petris MJ: Cisplatin Stabilizes a multimeric complex of the human Ctr1 copper transporter: requirement for the extracellular methionine-rich clusters. J Biol Chem 2004, 279:46393-46399.
• [18]Al-Eisawi Z, Beale P, Chan C, Yu JQ, Huq F: Modulation of cisplatin cytotoxicity due to its combination with bortezomib and the nature of its administration. Anticancer Res 2011, 31:2757-2762.
• [19]Goldberg AL: Development of proteasome inhibitors as research tools and cancer drugs. J Cell Biol 2012, 199:583-588.
• [20]Dou QP: Proteasome inhibition and cancer therapy. Nat Rev Cancer 2011., 11
• [21]Weniger MA, Rizzatti EG, Pérez-Galán P, Liu D, Wang Q, Munson PJ, Raghavachari N, White T, Tweito MM, Dunleavy K, Ye Y, Wilson WH, Wiestner A: Treatment-Induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. Clin Cancer Res 2011, 17:5101-5112.
• [22]Mujtaba T, Dou QP: Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med 2011, 12:471-480.
• [23]Crider SE, Holbrook RJ, Franz KJ: Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1. Metallomics 2010, 2:74-83.
• [24]Wang X, Li H, Du X, Harris J, Guo Z, Sun H: Activation of carboplatin and nedaplatin by the N-terminus of human copper transporter 1 (hCTR1). Chem Sci 2012, 3:3206-3215.
• [25]Chowdhury MA, Huq F, Abdullah A, Beale P, Fisher K: Synthesis, characterization and binding with DNA of four planaramineplatinum(II) complexes of the forms: trans-PtL2Cl2 and [PtL3Cl]Cl, where L = 3-hydroxypyridine, 4-hydroxypyridine and imidazo(1,2-α)pyridine. J Inorg Biochem 2005, 99:1098-1112.
• [26]Manzotti C, Pratesi G, Menta E, Di Domenico R, Cavalletti E, Fiebig HH, Kelland LR, Farrell N, Polizzi D, Supino R, Pezzoni G, Zunino F: BBR 3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin. Clin Cancer Res 2000, 6:2626-2634.
• [27]Huq F, Yu JQ, Beale P: Studies on New Platinum Compounds. In Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy. Edited by Bonetti A, Leone R, Muggia F, Howell S. New York: Humana Press; 2009:11-17.
• [28]Shah MA, Schwartz GK: The relevance of drug sequence in combination chemotherapy. Drug Resist Updat 2000, 3:335-356.
• [29]Chou TC: Drug combination studies and their synergy quantification using the chou-talalay method. Cancer Res 2010, 70:440-446.
• [30]Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006, 58:621-681.
• [31]Chou TC, Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984, 22:27-55.
• [32]Andre P, Cisternino S, Chiadmi F, Toledano A, Schlatter J, Fain O, Fontan J-E: Stability of bortezomib 1-mg/mL solution in plastic syringe and glass vial. Ann Pharmacother 2005, 39:1462-1466.
• [33]Go RS, Adjei AA: Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999, 17:409.
• [34]Barnham KJ, Djuran MI, Murdoch PS, Ranford JD, Sadler PJ: Ring-Opened adducts of the anticancer drug carboplatin with sulfur amino acids. Inorg Chem 1996, 35:1065-1072.
• [35]Alberts DS, Dorr RT: New Perspectives on an Old friend: optimizing carboplatin for the treatment of solid tumors. Oncologist 1998, 3:15-34.
• [36]Schurig JE, Rose WC, Catino JJ, Gaver RC, Long BH, Madissoo H, Canetta R: The Pharmacologic Characteristics of Carboplatin: Preclinical Experience. In Carboplatin (JM-8), Current Perspectives and Future Directions. Edited by Bunn PA, Canetta R, Ozols RF, Rosencweig M. Philadelphia: Saunders; 1990:3-17.
• [37]Sharma S, Gong P, Temple B, Bhattacharyya D, Dokholyan NV, Chaney SG: Molecular Dynamic simulations of cisplatin- and oxaliplatin-d(GG) intrastand cross-links reveal differences in their conformational dynamics. J Mol Biol 2007, 373:1123-1140.
• [38]Wu Y, Bhattacharyya D, King CL, Baskerville-Abraham I, Huh SH, Boysen G, Swenberg JA, Temple B, Campbell SL, Chaney SG: Solution Structures of a DNA dodecamer duplex with and without a cisplatin 1,2-d(GG) intrastrand cross-link: comparison with the same DNA duplex containing an oxaliplatin 1,2-d(GG) intrastrand cross-link. Biochemistry (Mosc) 2007, 46:6477-6487.
• [39]Ray-Coquard I, Weber B, Cretin J, Haddad-Guichard Z, Levy E, Hardy-Bessard AC, Gouttebel MC, Geay JF, Aleba A, Orfeuvre H, Agostini C, Provencal J, Ferrero JM, Fric D, Dohollou N, Paraiso D, Salvat J, Pujade-Lauraine E: Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group. Br J Cancer 2009, 100:601-607.
• [40]Yuan Z, Cao K, Lin C, Li L, Liu HY, Zhao XY, Liu L, Deng HX, Li J, Nie CL, Wei YQ: The p53 upregulated modulator of apoptosis (PUMA) chemosensitizes intrinsically resistant ovarian cancer cells to cisplatin by lowering the threshold set by Bcl-xL and Mcl-1. Mol Med 2011, 17:1262-1274.
• [41]Toscano F, Parmentier B, Fajoui ZE, Estornes Y, Chayvialle JA, Saurin JC, Abello J: p53 dependent and independent sensitivity to oxaliplatin of colon cancer cells. Biochem Pharmacol 2007, 74:392-406.
• [42]Aghajanian C, Dizon DS, Sabbatini P, Raizer JJ, Dupont J, Spriggs DR: Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J Clin Oncol 2005, 23:5943-5949.
• [43]Reed DJ: Glutathione: toxicological implications. Annu Rev Pharmacol Toxicol 1990, 30:603-631.
• [44]Taguchi Y, Yoshida A, Takada Y, Komano T, Ueda K: Anti-cancer drugs and glutathione stimulate vanadate-induced trapping of nucleotide in multidrug resistance-associated protein (MRP). FEBS Lett 1997, 401:11-14.