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A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells

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Abstract

Purpose

Overexpression of Bcl-2 family members as well as deregulated apoptosis pathways are known hallmarks of lung cancer. Non-small cell lung cancer (NSCLC) cells are typically resistant to cytotoxic chemotherapy and approaches that alter the balance between pro-survival and pro-death Bcl-2 family members have shown promise in preclinical models of NSCLC.

Methods

Here we evaluated the effects of a novel pan-Bcl-2 inhibitor GX15-070 on NSCLC survival and when combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as well as traditional cytotoxic agents. GX15-070 is a small molecule agent that binds anti-apoptotic Bcl-2 proteins and interferes with their ability to interact with pro-apoptotic proteins. We evaluated the effect of GX15-070 and correlated the effect on EGFR status as well as Bcl-2 family protein expression.

Results

We show that GX15-070 can disrupt Mcl-1:Bak interactions in lung cancer cells. We identified differential sensitivity of a panel of lung cancer cells to GX15-070 and no clear relationship existed between EGFR status or Bcl-2 family protein expression and sensitivity to GX15-070. GX15-070 could induce apoptosis in a subset of lung cancer cell lines and this correlated with the effects on cell viability. GX15-070 combined with gefitinib was synergistic in a cell line dependent on EGFR for survival but GX15-070 could not reverse resistance to gefitinib in cell lines not dependent on EGFR for survival. Finally, we observed synergy between GX15-070 and cisplatin in NSCLC cells.

Conclusions

Based on these results, GX15-070 can trigger apoptosis in NSCLC cells and can enhance chemotherapy-induced death. These data suggest that clinical trials with GX15-070 in combination with cytotoxic chemotherapy are indicated.

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References

  1. Haura EB, Cress WD, Chellappan S, Zheng Z, Bepler G (2004) Antiapoptotic signaling pathways in non-small-cell lung cancer: biology and therapeutic strategies. Clin Lung Cancer 6:113–122

    PubMed  CAS  Google Scholar 

  2. Reed JC (1996) Mechanisms of Bcl-2 family protein function and dysfunction in health and disease. Behring Inst Mitt 97:72–100

    PubMed  CAS  Google Scholar 

  3. Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci U S A 92:7834–7838

    Article  PubMed  CAS  Google Scholar 

  4. Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    Article  PubMed  CAS  Google Scholar 

  5. Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22:8590–8607

    Article  PubMed  CAS  Google Scholar 

  6. Anton RC, Brown RW, Younes M, Gondo MM, Stephenson MA, Cagle PT (1997) Absence of prognostic significance of bcl-2 immunopositivity in non-small cell lung cancer: analysis of 427 cases. Hum Pathol 28:1079–1082

    Article  PubMed  CAS  Google Scholar 

  7. Apolinario RM, van der Valk P, de Jong JS, Deville W, van Ark-Otte J, Dingemans AM, van Mourik JC, Postmus PE, Pinedo HM, Giaccone G (1997) Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer. J Clin Oncol 15:2456–2466

    PubMed  CAS  Google Scholar 

  8. Borner MM, Brousset P, Pfanner-Meyer B, Bacchi M, Vonlanthen S, Hotz MA, Altermatt HJ, Schlaifer D, Reed JC, Betticher DC (1999) Expression of apoptosis regulatory proteins of the Bcl-2 family and p53 in primary resected non-small-cell lung cancer. Br J Cancer 79:952–958

    Article  PubMed  CAS  Google Scholar 

  9. Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi M, Angeletti CA, Basolo F, Bevilacqua G (1995) Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small-cell lung cancer. Br J Cancer 71:1003–1007

    PubMed  CAS  Google Scholar 

  10. Gaffney EF, O’Neil AJ, Staunton MJ (1994) Bcl-2 and prognosis in non-small-cell lung carcinoma. N Engl J Med 330:1757–1758

    Article  PubMed  CAS  Google Scholar 

  11. Higashiyama M, Doi O, Kodama K, Yokouchi H, Tateishi R (1995) High prevalence of bcl-2 oncoprotein expression in small cell lung cancer. Anticancer Res 15:503–505

    PubMed  CAS  Google Scholar 

  12. Higashiyama M, Doi O, Kodama K, Yokouchi H, Tateishi R (1996) Bcl-2 oncoprotein expression is increased especially in the portion of small cell carcinoma within the combined type of small cell lung cancer. Tumour Biol 17:341–344

    Article  PubMed  CAS  Google Scholar 

  13. Higashiyama M, Doi O, Kodama K, Yokouchi H, Nakamori S, Tateishi R (1997) Bcl-2 oncoprotein in surgically resected non-small cell lung cancer: possibly favorable prognostic factor in association with low incidence of distant metastasis. J Surg Oncol 64:48–54

    Article  PubMed  CAS  Google Scholar 

  14. Ikegaki N, Katsumata M, Minna J, Tsujimoto Y (1994) Expression of bcl-2 in small cell lung carcinoma cells. Cancer Res 54:6–8

    PubMed  CAS  Google Scholar 

  15. Katz HR (1994) Bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 330:221

    Article  PubMed  CAS  Google Scholar 

  16. Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, Harris A, Gatter KC, Mason DY (1993) Bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 329:690–694

    Article  PubMed  CAS  Google Scholar 

  17. Ritter JH, Dresler CM, Wick MR (1995) Expression of bcl-2 protein in stage T1N0M0 non-small cell lung carcinoma. Hum Pathol 26:1227–1232

    Article  PubMed  CAS  Google Scholar 

  18. Sartorius UA, Krammer PH (2002) Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int J Cancer 97:584–592

    Article  PubMed  CAS  Google Scholar 

  19. Gautschi O, Tschopp S, Olie RA, Leech SH, Simoes-Wust AP, Ziegler A, Baumann B, Odermatt B, Hall J, Stahel RA, Zangemeister-Wittke U (2001) Activity of a novel bcl-2/bcl-xL-bispecific antisense oligonucleotide against tumors of diverse histologic origins. J Natl Cancer Inst 93:463–471

    Article  PubMed  CAS  Google Scholar 

  20. Kataoka M, Wiehle S, Spitz F, Schumacher G, Roth JA, Cristiano RJ (2000) Down-regulation of bcl-2 is associated with p16INK4-mediated apoptosis in non-small cell lung cancer cells. Oncogene 19:1589–1595

    Article  PubMed  CAS  Google Scholar 

  21. Koty PP, Zhang H, Levitt ML (1999) Antisense bcl-2 treatment increases programmed cell death in non-small cell lung cancer cell lines. Lung Cancer 23:115–127

    Article  PubMed  CAS  Google Scholar 

  22. Leech SH, Olie RA, Gautschi O, Simoes-Wust AP, Tschopp S, Haner R, Hall J, Stahel RA, Zangemeister-Wittke U (2000) Induction of apoptosis in lung-cancer cells following bcl-xL anti-sense treatment. Int J Cancer 86:570–576

    Article  PubMed  CAS  Google Scholar 

  23. Ouyang N, Ran P, Qiu Z (2000) [Bcl-2 antisense oligodeoxyribonucleotide increases apoptosis of lung carcinoma cells induced by cisplatin]. Zhonghua Jie He He Hu Xi Za Zhi 23:722–724

    PubMed  CAS  Google Scholar 

  24. Ziegler A, Luedke GH, Fabbro D, Altmann KH, Stahel RA, Zangemeister-Wittke U (1997) Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the Bcl-2 coding sequence. J Natl Cancer Inst 89:1027–1036

    Article  PubMed  CAS  Google Scholar 

  25. Janmaat ML, Kruyt FA, Rodriguez JA, Giaccone G (2003) Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 9:2316–2326

    PubMed  CAS  Google Scholar 

  26. Song L, Coppola D, Livingston S, Cress D, Haura EB (2005) Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. Cancer Biol Ther, 4:267–276

    Article  PubMed  CAS  Google Scholar 

  27. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885

    Article  PubMed  CAS  Google Scholar 

  28. Banerjee D (1999) Technology evaluation: G-3139. Curr Opin Mol Ther 1:404–408

    PubMed  CAS  Google Scholar 

  29. Banerjee D (2001) Genasense (Genta Inc). Curr Opin Investig Drugs 2:574–580

    PubMed  CAS  Google Scholar 

  30. Morris MJ, Tong WP, Cordon-Cardo C, Drobnjak M, Kelly WK, Slovin SF, Terry KL, Siedlecki K, Swanson P, Rafi M, DiPaola RS, Rosen N, Scher HI (2002) Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res 8:679–683

    PubMed  CAS  Google Scholar 

  31. Rudin CM, Otterson GA, Mauer AM, Villalona-Calero MA, Tomek R, Prange B, George CM, Szeto L, Vokes EE (2002) A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 13:539–545

    Article  PubMed  CAS  Google Scholar 

  32. Rudin CM, Kozloff M, Hoffman PC, Edelman MJ, Karnauskas R, Tomek R, Szeto L, Vokes EE (2004) Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 22:1110–1117

    Article  PubMed  CAS  Google Scholar 

  33. Reed JC, Pellecchia M (2005) Apoptosis-based therapies for hematologic malignancies. Blood 106:408–418

    Article  PubMed  CAS  Google Scholar 

  34. Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson BE, Janne PA (2004) Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 64:7241–7244

    Article  PubMed  CAS  Google Scholar 

  35. Fujimoto N, Wislez M, Zhang J, Iwanaga K, Dackor J, Hanna AE, Kalyankrishna S, Cody DD, Price RE, Sato M, Shay JW, Minna JD, Peyton M, Tang X, Massarelli E, Herbst R, Threadgill DW, Wistuba II, Kurie JM (2005) High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res 65:11478–11485

    Article  PubMed  CAS  Google Scholar 

  36. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102(21):7665–7670

    Article  PubMed  CAS  Google Scholar 

  37. Song L, Turkson J, Karras JG, Jove R, Haura EB (2003) Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22:4150–4165

    Article  PubMed  CAS  Google Scholar 

  38. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  PubMed  CAS  Google Scholar 

  39. Haura EB, Zheng Z, Song L, Cantor A, Bepler G (2005) Activated epidermal growth factor receptor-stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res 11:8288–8294

    Article  PubMed  CAS  Google Scholar 

  40. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  41. Sordella R, Bell DW, Haber DA, Settleman J (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163–1167

    Article  PubMed  CAS  Google Scholar 

  42. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:1–11

    Article  CAS  Google Scholar 

  43. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681

    Article  PubMed  CAS  Google Scholar 

  44. O’Brien S, Kipps TJ, Fader S, Crump M, Keating M, Anderson B, Soho C, Bole J, Turner R, Viallet J, Cheson B (2004) A phase I trial of the small molecule pan-bcl-2 family inhibitor GX15-070 administered intravenously (IV) every 3 weeks to patients with previously treated chronic lymphocytic leukemia (CLL). American Society of Hematology (ASH), Washington

    Google Scholar 

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Acknowledgments

We thank Dr Mark Watson (GeminX Biotechnologies Inc., Montreal, QC, Canada) for help with coimmunoprecipitation assays and Drs Pasi Janne (Dana Farber, Boston, MA, USA), Jon Kurie (MD Anderson, Houston, TX, USA), and Jeffrey Settleman (Massachusetts General Hospital Cancer Center, Boston, MA, USA) for providing cell lines. We thank Drs Warren Fiskus and Kapil Bhalla (Medical College of Georgia Cancer Center, Augusta, GA, USA) for help with synergy analysis, and Tiffany Dyn for administrative assistance. This work has been supported in part by the Molecular Imaging Core, Molecular Biology and Sequencing Core, and the Flow Cytometry Core at the H. Lee Moffitt Cancer Center & Research Institute. This work was partially funded by the H. Lee Moffitt Cancer Center & Research Institute.

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Correspondence to Eric B. Haura.

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Li, J., Viallet, J. & Haura, E.B. A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemother Pharmacol 61, 525–534 (2008). https://doi.org/10.1007/s00280-007-0499-3

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