Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines

Abstract

Farnesyltransferase inhibitor (FTI) induces apoptosis of transformed cells. This involves changes in mitochondria, including decrease of mitochondrial membrane potential and the release of cytochrome c. The released cytochrome c then induces events leading to the activation of caspase-3. In this study, we report that purine derivative cyclin-dependent kinase (Cdk) inhibitors, roscovitine and olomoucine, dramatically enhance this FTI-induced apoptosis of human cancer cell lines. We noticed the synergy between Cdk inhibitors and FTI through our screen to identify compounds that enhance FTI-induced apoptosis of promyelocytic leukemic cell line HL-60. The Cdk inhibitors by themselves do not induce apoptosis at the concentrations used. Roscovitine synergizes with FTI to release cytochrome c from mitochondria. In addition, we detected synergistic effects of FTI and roscovitine to inhibit hyperphosphorylation of retinoblastoma protein. Enhancement of FTI-induced apoptosis by roscovitine is not unique to HL-60 cells, since similar synergy was observed with a leukemic cell line CEM and a prostate cancer cell line LNCaP. In LNCaP cells, in addition to roscovitine and olomoucine, phophatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, was effective in enhancing FTI-induced apoptosis. However, the effects of roscovitine appear to be distinct from those of LY294002, since roscovitine did not affect Akt activity while LY294002 significantly decreased the activity of Akt. Our finding of the synergy between FTI and Cdk inhibitor is significant for understanding the mechanism of action of FTI as well as for clinical use of FTI.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P and Hemmings BA. . 1996 EMBO J. 15: 6541–6551.

  • Alessi DR, Cuenda A, Cohen P, Dudley DT and Saltiel AR. . 1995 J. Biol. Chem. 270: 27486–27494.

  • Barrington RE, Subler MA, Rands E, Omer CA, Miller PJ, Hundley JE, Koester SK, Troyer DA, Bearss DJ, Conner MW, Gibbs JB, Hamilton K, Koblan KS, Mosser SD, O'Neill TJ, Schaber MD, Senderak ET, Windle JJ, Oliff A and Kohl NE. . 1998 Mol. Cell. Biol. 18: 85–92.

  • Bishop WR, Bond R, Petrin J, Wang L, Patton R, Doll R, Njoroge G, Catino J, Schwartz J, Windsor W, Syto R, Schwartz J, Carr D, James L and Kirschmeier P. . 1995 J. Biol. Chem. 270: 30611–30618.

  • Chang Y-T, Gray NS, Rosania GR, Sutherlin DP, Kwon S, Norman TC, Sarohia R, Leost M, Meijer L and Schultz PG. . 1999 Chem. Biol. 6: 361–375.

  • Crompton M. . 1999 Biochem. J. 341: 233–249.

  • Der CJ, Cox AD, Sebti SM and Hamilton AD. . 1996 Anti-Cancer Drugs 7: 165–172.

  • Dou QP, An B and Will PL. . 1995 Proc. Natl. Acad. Sci. USA 92: 9019–9023.

  • Du W, Liu A and Prendergast GC. . 1999 Cancer Res. 59: 4208–4212.

  • Dudley DT, Pang L, Decker SJ, Bridges AJ and Saltiel. . 1995 Proc. Natl. Acad. Sci. USA 92: 7686–7689.

  • Garcia AM, Rowell C, Ackermann K, Kowalczyk JJ and Lewis MD. . 1993 J. Biol. Chem. 268: 18415–18418.

  • Gibbs JB and Oliff A. . 1997 Annu. Rev. Pharmacol. Toxicol. 37: 143–166.

  • Havlicek L, Hanus J, Vesely J, Leclerc S, Meijer L, Shaw G and Strand M. . 1997 J. Med. Chem. 40: 408–412.

  • Hung WC and Chuang LY. . 1998 Int. J. Oncol. 12: 137–140.

  • James GL, Goldstein JL, Brown MS, Rawson TE, Somers TC, McDowell RS, Crowley C, Lucas B, Levinson A and Masters JC. . 1993 Science 260: 1937–1942.

  • Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM and Cheng JQ. . 2000 Mol. Cell. Biol. 20: 139–148.

  • Kaelin Jr WG. . 1999 BioEssays 21: 950–958.

  • Kennedy SG, Kandel ES, Cross TK and Hay N. . 1999 Mol. Cell. Biol. 19: 5800–5810.

  • Kohl NE, Mosser SD, DeSolmes J, Giuliani EA, Pompliano DL, Graham SL, Smith RL, Scolnick EM, Oliff A and Gibbs JB. . 1993 Science 260: 1934–1993.

  • Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolmes SJ, Giuliani EA, Gomez RP, Graham SL, Hamilton K, Handt LK, Hartman GD, Koblan KS, Kral AM, Miller PJ, Mosser SD, O'Neill TJ, Rands E, Schaber MD, Gibbs JB and Oliff A. . 1995 Nature Med. 1: 792–797.

  • Knudsen KE, Weber E, Arden KC, Cavenee WK, Feramisco JR and Knudsen ES. . 1999 Oncogene 18: 5239–5245.

  • Lebowitz PF and Prendergast GC. . 1998 Oncogene 17: 1439–1445.

  • Lebowitz PF, Sakamuro D and Prendergast GC. . 1997 Cancer Res. 57: 708–713.

  • Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, Malkowski M, Ferrari E, Nielsen L, Prioli N, Dell J, Sinha D, Syed J, Korfmacher WA, Nomier AA, Lin C-C, Wang L, Taveras A, Doll RJ, Njoroge G, Mallams AK, Remiszewski S, Catino JJ, Girijavallabhan VM, Kirschmeier P and Bishop WR. . 1998 Cancer Res. 58: 4947–4956.

  • Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, Inagaki M, Delcros JG and Moulinoux JP. . 1997 Eur. J. Biochem. 243: 527–536.

  • Mittnacht S. . 1998 Curr. Opin. Genet. Dev. 8: 21–27.

  • Moasser MM, Sepp-Lorenzino L, Kohl NE, Oliff A, Balog A, Su DS, Danishefsky SJ and Rosen N. . 1998 Proc. Natl. Acad. Sci. USA 95: 1369–1374.

  • Nagasu T, Yoshimatsu K, Rowell C, Lewis MD and Garcia AM. . 1995 Cancer Res. 55: 5310–5314.

  • Norgaard P, Law B, Joseph MH, Page DL, Shyr Y, Mays D, Pietenpol JA, Kohl NE, Oliff A, Coffey RJ Jr, Poulsen HS and Moses HL. . 1999 Clin. Cancer Res. 5: 35–42.

  • Okada T, Saluma L, Fukui Y, Hazeki O and Ui M. . 1994 J. Biol. Chem. 269: 3563–3567.

  • Ongkeko W, Ferguson DJ, Harris AL and Norbury C. . 1995 J. Cell Sci. 108: 2897–2904.

  • Patel V, Senderowicz AM, Pinto D Jr, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA and Gutkind JS. . 1998 J. Clin. Invest. 102: 1674–1681.

  • Prendergast GC, Davide JP, deSolmes SJ, Giuliani EA, Graham SL, Gibbs JB, Oliff A and Kohl NE. . 1994 Mol. Cell. Biol. 14: 4193–4202.

  • Rowinsky EK, Windle JJ and Von Hoff DD. . 1999 J. Clin. Oncol. 17: 3631–3652.

  • Sattler I and Tamanoi F. . 1996 In Regulation of the RAS Signalling Network H Maruta and AW Burgess (eds). Molecular Biology Intelligence Unit Series RG Landes: Austin TX. pp. 95–137.

  • Sepp-Lorenzino L and Rosen N. . 1998 J. Biol. Chem. 273: 20243–20251.

  • Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff A and Rosen N. . 1995 Cancer Res. 55: 5302–5309.

  • Strickland CL, Weber PC, Windsor WT, Wu Z, Le HV, Albanese MM, Alvarez CS, Cesarz D, del Rosario J, Deskus J, Mallams AK, Nyoroge FG, Piwinski JJ, Remiszewski S, Rossman RR, Taveras AG, Vibulbhan B, Doll RJ, Girijavallabhan VM and Ganguly AK. . 1999 J. Med. Chem. 42: 2125–2135.

  • Sun J, Qian Y, Hamilton AD and Sebti SM. . 1995 Cancer Res. 55: 4243–4247.

  • Suzuki N, Del Villar K and Tamanoi F. . 1998a Proc. Natl. Acad. Sci. USA 95: 10499–10504.

  • Suzuki N, Urano J and Tamanoi F. . 1998b Proc. Natl. Acad. Sci. USA 95: 15356–15361.

  • Vesely J, Havlicek L, Strnad M, Blow JJ, Donella-Deana A, Pinna L, Letham DS, Kato J, Detivaud L, Leclerc S and Meijer L. . 1994 Eur. J. Biochem. 224: 771–778.

  • Vlahos CJ, Matter WF, Hui KY and Brown RF. . 1994 J. Biol. Chem. 269: 5241–5248.

  • Vogt A, Sun J, Qian Y, Hamilton AD and Sebti SM. . 1997 J. Biol. Chem. 272: 27224–27229.

  • Wolf D and Rotter V. . 1985 Proc. Natl. Acad. Sci. USA 82: 790–794.

  • Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsh T, Susin SA, Petit PX, Mignotte B and Kroemer G. . 1995 J. Exp. Med. 182: 367–377.

  • Zhang FL and Casey PJ. . 1996 Annu. Rev. Biochem. 65: 341–370.

  • Zou H, Li Y, Liu X and Wang X. . 1999 J. Biol. Chem. 274: 11549–11556.

Download references

Acknowledgements

We are grateful to Dr W Robert Bishop for providing us with SCH56582 and for discussions about this work. We also thank Drs Judith Gasson, Charles Sawyers and David Chang for critical reading of this paper. This work was supported by NIH grant CA41996. C-L Gau was supported by USPHS National Research Service Award GM07185. TN was a Research Scholar supported by the Ministry of Education, Science, Sport and Culture, Japan. We thank Ingrid Schmidt and Nathan Regimbal at the Jonsson Comprehensive Cancer Center Flow Cytometry Core Laboratory for flow cytometry.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Edamatsu, H., Gau, CL., Nemoto, T. et al. Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines. Oncogene 19, 3059–3068 (2000). https://doi.org/10.1038/sj.onc.1203625

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203625

Keywords

This article is cited by

Search

Quick links