Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Antitumor Activity of LB42907, a Potent and Selective Farnesyltransferase Inhibitor: Synergistic Effect in Combination with Other Anticancer Drugs

  • Published : 2008.07.20
Download PDF
⟨ Previous Next ⟩

Abstract

Inhibitors of farnesyltransferase (FT), a key enzyme in the post-translational modifications of Ras proteins, have been extensively studied as novel anticancer agents in the preclinical stages, some of which are currently in clinical development. Previously, it has been reported that a novel FT inhibitor LB42907 inhibits Ras farnesylation in the nanomolar range in vitro. The aim of this study was to assess the antitumor efficacy of LB42907 in vitro and in vivo. Anchorage-independent growth of various human tumor cell lines was potently inhibited by treatment with LB42907, comparable to other FT inhibitors in clinical development. In the nude mouse, oral administration of LB42907 demonstrated potent antitumor activity in several human tumor xenograft models including bladder, lung and pancreas origin. Interestingly, significant tumor regression in EJ (bladder) and A549 (lung) xenografts was induced by LB42907 treatment. The effectiveness of LB42907 was also investigated in simultaneous combination with paclitaxel, vincristine, cisplatin or gemcitabine against NCI-H460, A549, and HCT116 cells in vitro using median-effect analysis. LB42907 markedly synergized with most anticancer drugs tested in this study in NCI-H460 cell. In contrast, LB42907 displayed antagonism or partial synergism with these drugs in A549 and HCT116 cells, depending on the class of combined drugs and/ or the level of cytotoxicity. Our results demonstrate that LB42907 is an effective antitumor agent in vitro and in vivo and combination of LB42907 with other chemotherapeutic drugs results in synergistic or antagonistic effects mainly in a cell line-dependent manner. Further preclinical study is warranted.

Keywords

References

  1. Barbacid, M. Annu. Rev. Biochem. 1987, 56, 779 https://doi.org/10.1146/annurev.bi.56.070187.004023
  2. Bos, J. L. Cancer Res. 1989, 49, 4682
  3. Lowy, D. R.; Willumsen, B. M. Annu. Rev. Biochem. 1993, 62, 851 https://doi.org/10.1146/annurev.bi.62.070193.004223
  4. Cox, A. D.; Der, C. J. Crit. Rev. Oncog. 1992, 3, 365
  5. Gibbs, J. B.; Oliff, A.; Kohl, N. E. Cell 1994, 77, 175 https://doi.org/10.1016/0092-8674(94)90308-5
  6. Rowinsky, E. K.; Windle, J. J.; Von Hoff, D. J. Clin. Oncol. 1999, 17, 3631 https://doi.org/10.1200/JCO.1999.17.11.3631
  7. Prendergast, G. C. Lancet. Oncol. 2000, 1, 73 https://doi.org/10.1016/S1470-2045(00)00073-5
  8. Caponigro, F.; Casale, M.; Bryce, J. Expert. Opin. Investig. Drugs. 2003, 12, 943 https://doi.org/10.1517/13543784.12.6.943
  9. Head, J. E.; Johnston, S. R. Expert. Opin. Emerg. Drugs. 2003, 8, 163 https://doi.org/10.1517/14728214.8.1.163
  10. Adjei, A. A.; Croghan, G. A.; Erlichman, C.; Marks, R. S.; Reid, J. M.; Sloan, J. A.; Pitot, H. C.; Alberts, S. R.; Goldberg, R. M.; Hanson, L. J.; Bruzek, L. M.; Atherton, P. et al. Clin. Cancer. Res. 2003, 9, 2520
  11. Adjei, A. A.; Davis, J. N.; Bruzek, L. M.; Erlichman, C.; Kaufmann, S. H. Clin. Cancer Res. 2001, 7, 1438
  12. Shi, B.; Yaremko, B.; Hajian, G.; Terracina, G.; Bishop, W. R.; Liu, M.; Nielsen, L. L. Cancer Chemother. Pharmacol. 2000, 46, 387 https://doi.org/10.1007/s002800000170
  13. Lee, H.; Lee, J.; Lee, S.; Shin, Y.; Jung, W.; Kim, J. H.; Park, K.; Kim, K.; Cho, H. S.; Ro, S.; Lee, S.; Jeong, S. W.; Choi, T.; Chung, H. H.; Koh, J. S. Bioorg. Med. Chem. Lett. 2001, 11, 3069 https://doi.org/10.1016/S0960-894X(01)00624-2
  14. Njoroge, F. G.; Taveras, A. G.; Kelly, J.; Remiszewski, S.; Mallams, A. K.; Wolin, R.; Afonso, A.; Cooper, A. B.; Rane, D. F.; Liu, Y. T.; Wong, J.; Vibulbhan, B. et al. J. Med. Chem. 1998, 41, 4890 https://doi.org/10.1021/jm980462b
  15. WO 9716443 A1
  16. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Nat. Cancer. Inst. 1990, 82, 1107 https://doi.org/10.1093/jnci/82.13.1107
  17. Chou, T. C.; Talalay, P. Adv. Enzyme Regul. 1984, 22, 27 https://doi.org/10.1016/0065-2571(84)90007-4
  18. Liu, M.; Bryant, M. S.; Chen, J.; Lee, S.; Yaremko, B.; Lipari, P.; Malkowski, M.; Ferrari, E.; Nielsen, L.; Prioli, N.; Dell, J.; Sinha, D. et al. Cancer Res. 1998, 58, 4947
  19. Kohl, N. E.; Omer, C. A.; Conner, M. W.; Anthony, N. J.; Davide, J. P.; deSolms, S. J.; Giuliani, E. A.; Gomez, R. P.; Graham, S. L.; Hamilton, K.; Handt, L. K.; Hartman, G. D. et al. Nat. Med. 1995, 1, 792 https://doi.org/10.1038/nm0895-792
  20. Nakamura, K.; Yamaguch, A.; Namiki, M.; Ishihara, H.; Nagasu, T.; Kowalczyk, J. J.; Garcia, A. M.; Lewis, M. D.; Yoshimatsu, K. Oncol. Res. 2000, 12, 477
  21. Lebowitz, P. F.; Sakamuro, D.; Prendergast, G. C. Cancer Res. 1997, 57, 708
  22. Barrington, R. E.; Subler, M. A.; Rands, E.; Omer, C. A.; Miller, P. J.; Hundley, J. E.; Koester, S. K.; Troyer, D. A.; Bearss, D. J.; Conner, M. W.; Gibbs, J. B.; Hamilton, K. et al. Mol. Cell. Biol. 1998, 18, 85 https://doi.org/10.1128/MCB.18.1.85
  23. Du, W.; Liu, A.; Prendergast, G. C. Cancer Res. 1999, 59, 4208
  24. Nagasu, T.; Yoshimatsu, K.; Rowell, C.; Lewis, M. D.; Garcia, A. M. Cancer Res. 1995, 55, 5310
  25. Sepp-Lorenzino, L.; Ma, Z.; Rands, E.; Kohl, N. E.; Gibbs, J. B.; Oliff, A.; Rosen, N. Cancer Res. 1995, 55, 5302
  26. James, G.; Goldstein, J. L.; Brown, M. S. Proc. Natl. Acad. Sci. USA 1996, 93, 4454
  27. Rowell, C. A.; Kowalczyk, J. J.; Lewis, M. D.; Garcia, A. M. J. Biol. Chem. 1997, 272, 14093 https://doi.org/10.1074/jbc.272.22.14093
  28. Whyte, D. B.; Kirschmeier, P.; Hockenberry, T. N.; Nunez-Oliva, I.; James, L.; Catino, J. J.; Bishop, W. R.; Pai, J. K. J. Biol. Chem. 1997, 272, 14459 https://doi.org/10.1074/jbc.272.22.14459
  29. Sepp-Lorenzino, L.; Rosen, N. J. Biol. Chem. 1998, 273, 20243 https://doi.org/10.1074/jbc.273.32.20243
  30. Loprevite, M.; Favoni, R. E.; De Cupis, A.; Scolaro, T.; Semino, C.; Mazzanti, P.; Ardizzoni, A. Oncol. Rep. 2004, 11, 407
  31. Moasser, M. M.; Sepp-Lorenzino, L.; Kohl, N. E.; Oliff, A.; Balog, A.; Su, D. S.; Danishefsky, S. J.; Rosen, N. Proc. Natl. Acad. Sci. USA 1998, 95, 1369
  32. Russo, P.; Malacarne, D.; Falugi, C.; Trombino, S.; O'Connor, P. M. Int. J. Cancer 2002, 100, 266 https://doi.org/10.1002/ijc.10461
  33. Sun, J.; Blaskovich, M. A.; Knowles, D.; Qian, Y.; Ohkanda, J.; Bailey, R. D.; Hamilton, A. D.; Sebti, S. M. Cancer Res. 1999, 59, 4919
  34. Giannakakou, P.; Robey, R.; Fojo, T.; Blagosklonny, M. V. Oncogene 2001, 20, 3806 https://doi.org/10.1038/sj.onc.1204487
  35. Ashar, H. R.; James, L.; Gray, K.; Carr, D.; McGuirk, M.; Maxwell, E.; Black, S.; Armstrong, L.; Doll, R. J.; Taveras, A. G.; Bishop, W. R.; Kirschmeier, P. Exp. Cell Res. 2001, 262, 17 https://doi.org/10.1006/excr.2000.5076
  36. Thissen, J. A.; Gross, J. M.; Subramanian, K.; Meyer, T.; Casey, P. J. J. Biol. Chem. 1997, 272, 30362 https://doi.org/10.1074/jbc.272.48.30362