Antihelminthic benzimidazoles potentiate navitoclax (ABT-263) activity by inducing Noxa-dependent apoptosis in non-small cell lung cancer (NSCLC) cell lines

Cancer Cell International

Anahita Bhathena¹  Joel D Leverson¹  John Xue¹  Haichao Zhang¹  Lloyd T Lam² 

[1] Oncology Research, Abbvie, 1 North Waukegan Road, North Chicago 60064-6098, IL, USA;AbbVie, Tumor Genomics, bldg AP-10, dept R4CD, AbbVie, 1 North Waukegan Road, North Chicago 60064-6098, IL, USA

关键词: Apoptosis;    Caspase;    Navitoclax;    Benzimidazoles;   

Others  :  1138651
DOI  :  10.1186/s12935-014-0151-3

 received in 2014-10-23, accepted in 2014-12-19,  发布年份 2015

【 摘 要 】

Background

Evasion of apoptosis is a hallmark of cancer cells. One mechanism to deregulate the apoptotic pathway is by upregulation of the anti-apoptotic Bcl-2 family members. Navitoclax (ABT-263) is a Bcl-2/Bcl-x_L inhibitor that restores the ability of cancer cells to undergo apoptosis.

Methods

In this study we performed a high-throughput screen with 640 FDA-approved drugs to identify potential therapeutic combinations with navitoclax in a non-small cell lung cancer (NSCLC) cell line.

Results

Other than a panel of cancer compounds such as doxorubicin, camptothecin, and docetaxel, four antihelminthic compounds (benzimidazoles) potentiated navitoclax activity. Treatment with benzimidazoles led to induction of the pro-apoptotic protein Noxa at the mRNA and protein level. Noxa binds and antagonizes antiapoptotic protein Mcl-1. siRNA-mediated knock-down of Noxa completely rescued benzimidazole-potentiated navitoclax activity. In addition, inhibiting caspase 3 and 9 partially rescued benzimidazole-potentiated navitoclax activity.

Conclusions

We have identified compounds and mechanisms which potentiate navitoclax activity in lung cancer cell lines. Further validation of the benzimidazole-potentiated navitoclax effect in vivo is required to evaluate the potential for translating this observation into clinical benefit.

【 授权许可】

   
2015 Lam et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70.
• [2]Cory S, Huang DC, Adams JM: The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 2003, 22:8590-607.
• [3]Reed JC, Doctor KS, Godzik A: The domains of apoptosis: a genomics perspective. Sci STKE 2004, 2004:re9.
• [4]Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, et al.: Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005, 17:393-403.
• [5]Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al.: ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008, 68:3421-8.
• [6]Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, et al.: Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 2011, 29:909-16.
• [7]Tahir SK, Yang X, Anderson MG, Morgan-Lappe SE, Sarthy AV, Chen J, et al.: Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res 2007, 67:1176-83.
• [8]Chen S, Dai Y, Harada H, Dent P, Grant S: Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res 2007, 67:782-91.
• [9]Keuling AM, Felton KE, Parker AA, Akbari M, Andrew SE, Tron VA: RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway. PLoS One 2009, 4:e6651.
• [10]Tagscherer KE, Fassl A, Campos B, Farhadi M, Kraemer A, Bock BC, et al.: Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene 2008, 27:6646-56.
• [11]Lin X, Morgan-Lappe S, Huang X, Li L, Zakula DM, Vernetti LA, et al.: ‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene 2007, 26:3972-9.
• [12]Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, et al.: The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology 2010, 52:1310-21.
• [13]Reynoso D, Nolden LK, Yang D, Dumont SN, Conley AP, Dumont AG, et al.: Synergistic induction of apoptosis by the Bcl-2 inhibitor ABT-737 and imatinib mesylate in gastrointestinal stromal tumor cells. Mol Oncol 2011, 5:93-104.
• [14]Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A: Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 2007, 4:1681-9. discussion 1690
• [15]Gong Y, Somwar R, Politi K, Balak M, Chmielecki J, Jiang X, et al.: Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med 2007, 4:e294.
• [16]Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, et al.: Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 2013, 23:121-8.
• [17]Tan N, Wong M, Nannini MA, Hong R, Lee LB, Price S, et al.: Bcl-2/Bcl-xL inhibition increases the efficacy of MEK inhibition alone and in combination with PI3 kinase inhibition in lung and pancreatic tumor models. Mol Cancer Ther 2013, 12:853-64.
• [18]Okumura K, Huang S, Sinicrope FA: Induction of Noxa sensitizes human colorectal cancer cells expressing Mcl-1 to the small-molecule Bcl-2/Bcl-xL inhibitor, ABT-737. Clin Cancer Res 2008, 14:8132-42.
• [19]Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al.: Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 2012, 30:488-96.
• [20]Zhang H, Guttikonda S, Roberts L, Uziel T, Semizarov D, Elmore SW, et al.: Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines. Oncogene 2011, 30:1963-8.
• [21]Chen J, Jin S, Abraham V, Huang X, Liu B, Mitten MJ, et al.: The Bcl-2/Bcl-XL/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents In vitro and In vivo. Mol Cancer Ther 2011, 10:2340-9.
• [22]Vuitton DA: Benzimidazoles for the treatment of cystic and alveolar echinococcosis: what is the consensus? Expert Rev Anti Infect Ther 2009, 7:145-9.
• [23]Lopez H, Zhang L, George NM, Liu X, Pang X, Evans JJ, et al.: Perturbation of the Bcl-2 network and an induced Noxa/Bcl-xL interaction trigger mitochondrial dysfunction after DNA damage. J Biol Chem 2010, 285:15016-26.
• [24]Flagella M, Bui S, Zheng Z, Nguyen CT, Zhang A, Pastor L, et al.: A multiplex branched DNA assay for parallel quantitative gene expression profiling. Anal Biochem 2006, 352:50-60.
• [25]Mukhopadhyay T, Sasaki J, Ramesh R, Roth JA: Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Cancer Res 2002, 8:2963-9.
• [26]Pourgholami MH, Woon L, Almajd R, Akhter J, Bowery P, Morris DL: In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole. Cancer Lett 2001, 165:43-9.
• [27]Doudican N, Rodriguez A, Osman I, Orlow SJ: Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol Cancer Res 2008, 6:1308-15.
• [28]Sasaki J, Ramesh R, Chada S, Gomyo Y, Roth JA, Mukhopadhyay T: The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells. Mol Cancer Ther 2002, 1:1201-9.
• [29]Chu SW, Badar S, Morris DL, Pourgholami MH: Potent inhibition of tubulin polymerisation and proliferation of paclitaxel-resistant 1A9PTX22 human ovarian cancer cells by albendazole. Anticancer Res 2009, 29:3791-6.
• [30]Pourgholami MH, Szwajcer M, Chin M, Liauw W, Seef J, Galettis P, et al.: Phase I clinical trial to determine maximum tolerated dose of oral albendazole in patients with advanced cancer. Cancer Chemother Pharmacol 2010, 65:597-605.
• [31]Spagnuolo PA, Hu J, Hurren R, Wang X, Gronda M, Sukhai MA, et al.: The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood 2010, 115:4824-33.
• [32]Hauck P, Chao BH, Litz J, Krystal GW: Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737. Mol Cancer Ther 2009, 8:883-92.
• [33]Zall H, Weber A, Besch R, Zantl N, Hacker G: Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1. Mol Cancer 2010, 9:164. BioMed Central Full Text
• [34]Weber A, Kirejczyk Z, Potthoff S, Ploner C, Hacker G: Endogenous noxa determines the strong proapoptotic synergism of the BH3-mimetic ABT-737 with chemotherapeutic agents in human melanoma cells. Transl Oncol 2009, 2:73-83.
• [35]Li R, Zang Y, Li C, Patel NS, Grandis JR, Johnson DE: ABT-737 synergizes with chemotherapy to kill head and neck squamous cell carcinoma cells via a Noxa-mediated pathway. Mol Pharmacol 2009, 75:1231-9.
• [36]Miller LA, Goldstein NB, Johannes WU, Walton CH, Fujita M, Norris DA, et al.: BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis. J Invest Dermatol 2009, 129:964-71.
• [37]Tahir SK, Wass J, Joseph MK, Devanarayan V, Hessler P, Zhang H, et al.: Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines. Mol Cancer Ther 2010, 9:545-57.
• [38]Carette JE, Guimaraes CP, Wuethrich I, Blomen VA, Varadarajan M, Sun C, et al.: Global gene disruption in human cells to assign genes to phenotypes by deep sequencing. Nat Biotechnol 2011, 29:542-6.
• [39]Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, et al.: Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000, 288:1053-8.
• [40]Nikiforov MA, Riblett M, Tang WH, Gratchouck V, Zhuang D, Fernandez Y, et al.: Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proc Natl Acad Sci U S A 2007, 104:19488-93.
• [41]Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E, Colomer D: The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 2006, 107:257-64.
• [42]Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, et al.: ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci U S A 2009, 106:2200-5.
• [43]Albershardt TC, Salerni BL, Soderquist RS, Bates DJ, Pletnev AA, Kisselev AF, et al.: Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem 2011, 286:24882-95.
• [44]Berenbaum MC: Criteria for analyzing interactions between biologically active agents. Adv Cancer Res 1981, 35:269-335.