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Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737

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Abstract

Background

Oxaliplatin is frequently used in the treatment of metastatic colorectal cancer (CRC). Our previous work shows that oxaliplatin induces the pro-apoptotic protein Noxa in CRC cells. The Bcl2-inhibitor ABT-737 is particularly effective in cells with high Noxa levels. Therefore, we tested whether oxaliplatin and ABT-737 display synergy in killing CRC cells.

Methods

A panel of CRC cell lines was treated with oxaliplatin and ABT-737, either alone or in combination. Apoptosis was measured by FACS analysis of sub-G1 DNA content and by Western blot analysis of caspase-3 processing. Noxa expression was suppressed by lentiviral RNA interference.

Results

Oxaliplatin and ABT-737 displayed a strong synergistic apoptotic response, which was dependent on wildtype TP53 and oncogenic KRAS. TP53 and KRAS were required for drug-induced Noxa expression and this was essential for tumor cell apoptosis. Oxaliplatin, but not ABT-737, induced p53 accumulation, but both drugs stimulated Noxa expression. Combination treatment of mice with subcutaneous tumor xenografts drastically reduced tumor volume, while single drug treatment had no effect.

Conclusion

ABT-737 synergizes with oxaliplatin to kill colorectal cancer cells. This requires induction of Noxa by wildtype TP53 and oncogenic KRAS. Future studies should explore the anti-tumor efficacy of this drug combination in mouse models for spontaneous CRC development and in patient-derived tumor cell cultures and xenografts.

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References

  1. K. Bray, H.Y. Chen, C.M. Karp, M. May, S. Ganesan, V. Karantza-Wadsworth, R.S. DiPaola, E. White, Bcl-2 modulation to activate apoptosis in prostate cancer. Mol. Cancer Res. 7, 1487–1496 (2009)

    Article  PubMed  CAS  Google Scholar 

  2. L. Chen, S.N. Willis, A. Wei, B.J. Smith, J.I. Fletcher, M.G. Hinds, P.M. Colman, C.L. Day, J.M. Adams, D.C. Huang, Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17, 393–403 (2005)

    Article  PubMed  CAS  Google Scholar 

  3. D. Cunningham, W. Atkin, H.J. Lenz, H.T. Lynch, B. Minsky, B. Nordlinger, N. Starling, Colorectal cancer. Lancet 375, 1030–1047 (2010)

    Article  PubMed  Google Scholar 

  4. M.T. de Bruijn, D.A. Raats, F.J. Hoogwater, W.J. van Houdt, K. Cameron, J.P. Medema, I.H.M. Borel Rinkes, O. Kranenburg, Oncogenic KRAS sensitises colorectal tumour cells to chemotherapy by p53-dependent induction of Noxa. Br. J. Cancer 102, 1254–1264 (2010)

    Article  PubMed  Google Scholar 

  5. A. Hadji, C. Clybouw, M.T. Auffredou, C. Alexia, K. Poalas, A. Burlion, O. Feraud, G. Leca, A. Vazquez, Caspase-3 triggers a TPCK-sensitive protease pathway leading to degradation of the BH3-only protein puma. Apoptosis 2010

  6. P. Hauck, B.H. Chao, J. Litz, G.W. Krystal, Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737. Mol. Cancer Ther. 8, 883–892 (2009)

    Article  PubMed  CAS  Google Scholar 

  7. L.M. High, B. Szymanska, U. Wilczynska-Kalak, N. Barber, R. O’Brien, S.L. Khaw, I.B. Vikstrom, A.W. Roberts, R.B. Lock, The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs. Mol. Pharmacol. 77, 483–494 (2010)

    Article  PubMed  CAS  Google Scholar 

  8. M.H. Kang, Z. Wan, Y.H. Kang, R. Sposto, C.P. Reynolds, Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines: Mcl-1 inactivation. J. Natl Cancer Inst. 100, 580–595 (2008)

    Article  PubMed  CAS  Google Scholar 

  9. A.M. Keuling, K.E. Felton, A.A. Parker, M. Akbari, S.E. Andrew, V.A. Tron, RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway. PLoS ONE 4, e6651 (2009)

    Article  PubMed  Google Scholar 

  10. M. Konopleva, R. Contractor, T. Tsao, I. Samudio, P.P. Ruvolo, S. Kitada, X. Deng, D. Zhai, Y.X. Shi, T. Sneed, M. Verhaegen, M. Soengas, V.R. Ruvolo, T. McQueen, W.D. Schober, J.C. Watt, T. Jiffar, X. Ling, F.C. Marini, D. Harris, M. Dietrich, Z. Estrov, J. McCubrey, W.S. May, J.C. Reed, M. Andreeff, Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375–388 (2006)

    Article  PubMed  CAS  Google Scholar 

  11. J. Kuroda, S. Kimura, M. Andreeff, E. Ashihara, Y. Kamitsuji, A. Yokota, E. Kawata, M. Takeuchi, R. Tanaka, Y. Murotani, Y. Matsumoto, H. Tanaka, A. Strasser, M. Taniwaki, T. Maekawa, ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. Br. J. Haematol. 140, 181–190 (2008)

    PubMed  CAS  Google Scholar 

  12. X. Lin, S. Morgan-Lappe, X. Huang, L. Li, D.M. Zakula, L.A. Vernetti, S.W. Fesik, Y. Shen, ‘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 26, 3972–3979 (2007)

    Article  PubMed  CAS  Google Scholar 

  13. L.A. Miller, N.B. Goldstein, W.U. Johannes, C.H. Walton, M. Fujita, D.A. Norris, Y.G. Shellman, BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis. J. Invest. Dermatol. 129, 964–971 (2009)

    Article  PubMed  CAS  Google Scholar 

  14. K. Okumura, S. Huang, F.A. Sinicrope, 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. 14, 8132–8142 (2008)

    Article  PubMed  CAS  Google Scholar 

  15. T. Oltersdorf, S.W. Elmore, A.R. Shoemaker, R.C. Armstrong, D.J. Augeri, B.A. Belli, M. Bruncko, T.L. Deckwerth, J. Dinges, P.J. Hajduk, M.K. Joseph, S. Kitada, S.J. Korsmeyer, A.R. Kunzer, A. Letai, C. Li, M.J. Mitten, D.G. Nettesheim, S. Ng, P.M. Nimmer, J.M. O’Connor, A. Oleksijew, A.M. Petros, J.C. Reed, W. Shen, S.K. Tahir, C.B. Thompson, K.J. Tomaselli, B. Wang, M.D. Wendt, H. Zhang, S.W. Fesik, S.H. Rosenberg, An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005)

    Article  PubMed  CAS  Google Scholar 

  16. B. Pandit, A.L. Gartel, New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancer. Prostate 70, 825–833 (2010)

    PubMed  CAS  Google Scholar 

  17. T. Shibue, S. Suzuki, H. Okamoto, H. Yoshida, Y. Ohba, A. Takaoka, T. Taniguchi, Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways. EMBO J. 25, 4952–4962 (2006)

    Article  PubMed  CAS  Google Scholar 

  18. S. Shirasawa, M. Furuse, N. Yokoyama, T. Sasazuki, Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260, 85–88 (1993)

    Article  PubMed  CAS  Google Scholar 

  19. N. Smakman, L.M. Veenendaal, P. van Diest, R. Bos, R. Offringa, I.H.M. Borel Rinkes, O. Kranenburg, Dual effect of Kras(D12) knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy. Oncogene 24, 8338–8342 (2005)

    Article  PubMed  CAS  Google Scholar 

  20. K.E. Tagscherer, A. Fassl, B. Campos, M. Farhadi, A. Kraemer, B.C. Bock, S. her-Goeppinger, B. Radlwimmer, O.D. Wiestler, C. Herold-Mende, W. Roth, Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene 27, 6646–6656 (2008)

    Article  PubMed  CAS  Google Scholar 

  21. S.K. Tahir, X. Yang, M.G. Anderson, S.E. Morgan-Lappe, A.V. Sarthy, J. Chen, R.B. Warner, S.C. Ng, S.W. Fesik, S.W. Elmore, S.H. Rosenberg, C. Tse, Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 67, 1176–1183 (2007)

    Article  PubMed  CAS  Google Scholar 

  22. M.F. van Delft, A.H. Wei, K.D. Mason, C.J. Vandenberg, L. Chen, P.E. Czabotar, S.N. Willis, C.L. Scott, C.L. Day, S. Cory, J.M. Adams, A.W. Roberts, D.C. Huang, The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389–399 (2006)

    Article  PubMed  Google Scholar 

  23. A. Weber, Z. Kirejczyk, S. Potthoff, C. Ploner, G. Hacker, Endogenous noxa determines the strong proapoptotic synergism of the BH3-mimetic ABT-737 with chemotherapeutic agents in human melanoma cells. Transl. Oncol. 2, 73–83 (2009)

    PubMed  Google Scholar 

  24. E. Wesarg, S. Hoffarth, R. Wiewrodt, M. Kroll, S. Biesterfeld, C. Huber, M. Schuler, Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. Int. J. Cancer 121, 2387–2394 (2007)

    Article  PubMed  CAS  Google Scholar 

  25. S.N. Willis, J.M. Adams, Life in the balance: how BH3-only proteins induce apoptosis. Curr. Opin. Cell Biol. 17, 617–625 (2005)

    Article  PubMed  CAS  Google Scholar 

  26. H. Xu, G.W. Krystal, Actinomycin D decreases Mcl-1 expression and acts synergistically with ABT-737 against small cell lung cancer cell lines. Clin. Cancer Res. 2010

  27. D. Yecies, N.E. Carlson, J. Deng, A. Letai, Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 115, 3304–3313 (2010)

    Article  PubMed  CAS  Google Scholar 

  28. H. Zall, A. Weber, R. Besch, N. Zantl, G. Hacker, 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 9, 164 (2010)

    PubMed  Google Scholar 

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Acknowledgements

This study was supported by grants from the Association for International Cancer Research (07–552 to MTdB), the Vanderes Foundation (07–177 to DAER) and the Dutch Cancer Society (2009–4367 to EJAS and 2009–4367 to BLE)

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Authors and Affiliations

  1. Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands

    Daniëlle A. E. Raats, Menno T. de Bruijn, Ernst J. A. Steller, Benjamin L. Emmink, Inne H. M. Borel-Rinkes & Onno Kranenburg

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  1. Daniëlle A. E. Raats
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  2. Menno T. de Bruijn
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  3. Ernst J. A. Steller
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  4. Benjamin L. Emmink
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  6. Onno Kranenburg
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Corresponding author

Correspondence to Onno Kranenburg.

Additional information

Daniëlle A. E. Raats and Menno T. de Bruijn contributed equally to this manuscript

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Raats, D.A.E., de Bruijn, M.T., Steller, E.J.A. et al. Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737. Cell Oncol. 34, 307–313 (2011). https://doi.org/10.1007/s13402-011-0026-8

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  • DOI: https://doi.org/10.1007/s13402-011-0026-8

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