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.

  • Review Article
  • Published:

Review Article

Bcl-2 family proteins as targets for anticancer drug design

Abstract

Bcl-2 family proteins are key regulators of programmed cell death or apoptosis that is implicated in many human diseases, particularly cancer. In recent years, they have attracted intensive interest in both basic research to understand the fundamental principles of cell survival and cell death and drug discovery to develop a new class of anticancer agents. The Bcl-2 family includes both anti- and pro-apoptotic proteins with opposing biological functions in either inhibiting or promoting cell death. High expression of anti-apoptotic members such as Bcl-2 and Bcl-xL commonly found in human cancers contributes to neoplastic cell expansion and interferes with the therapeutic action of many chemotherapeutic drugs. The functional blockade of Bcl-2 or Bcl-xL could either restore the apoptotic process in tumor cells or sensitize these tumors for chemo- and radiotherapies. This article reviews the recent progress in the design and discovery of small molecules that block the anti-apoptotic function of Bcl-2 or Bcl-xL. These chemical inhibitors are effective modulators of apoptosis and promising leads for the further development of new anticancer agents.

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

Similar content being viewed by others

References

  • Adams J and Cory S. . 1998 Science 281: 1322–1326.

  • Aritomi M, Kunishima N, Inohara N, Ishibashi Y, Ohta S and Morikawa K. . 1997 J. Biol. Chem. 272: 27886–27892.

  • Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstrom S, Avery BJ, Ebb RG, Subramanian T, Chittenden T, Lutz RJ, Chinnadurai G. . 1995 Oncogene 11: 1921–1928.

  • Chao D and Korsmeyer S. . 1998 Annu. Rev. Immunol. 16: 395–419.

  • Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G and Lutz RJ. . 1995 EMBO J. 14: 5589–5596.

  • Chou JJ, Li H, Salvesen GS, Yuan J and Wagner G. . 1999 Cell 96: 615–624.

  • Cosulich S, Worrall V, Hedge P, Green S and Clarke P. . 1997 Curr. Biol. 7: 913–920.

  • Diaz JL, Oltersdorf T, Horne W, McConnell M, Wilson G, Weeks S, Garcia T and Fritz LC. . 1997 J. Biol. Chem. 272: 11350–11355.

  • Holinger EP, Chittenden T and Lutz RJ. . 1999 J. Biol. Chem. 274: 13298–13304.

  • Huang Z. . 2000 Pharmacol. Therapeu. 86: 201–215.

  • Jansen B, Schlagbauer-Wadl H, Brown B, Bryan R, van Elsas A, Muller M, Wolff K, Eichler H and Pehamberger H. . 1998 Nat. Med. 4: 232–234.

  • Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D and Reed JC. . 1998 Proc. Natl. Acad. Sci. USA 95: 4997–5002.

  • Kelekar A, Chang B, Harlan J, Fesik S and Thompson C. . 1997 Mol. Cell Biol. 17: 7040–7046.

  • McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ and Cowburn D. . 1999 Cell 96: 625–634.

  • Morgan BA, Finnegan NM, Prevost G and Cotter TG. . 2000 91st Ann. Meet. Am. Assoc. Cancer Res. 42: 4693.

  • Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Chang BS, Thompson CB, Wong SL, Ng SL and Fesik SW. . 1996 Nature 381: 335–341.

  • Nakashima T, Miura M and Hara M. . 2000 Cancer Res. 60: 1229–1235.

  • Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H and Tsujimoto Y. . 1998 Proc. Natl. Acad. Sci. USA 95: 14681–14686.

  • Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G, Chang S, Weeks S, Fritz LC and Oltersdorf T. . 1997 J. Biol. Chem. 272: 30866–30872.

  • Piche A, Grim J, Rancourt C, Gomez-Navarro J, Reed JC and Curiel DT. . 1998 Cancer Res. 58: 2134–2140.

  • Reed JC. . 1994 J. Cell Biol. 124: 1–6.

  • Reed JC, Miyashita T, Takayama S, Wang HG, Sato T, Krajewski S, Aime-Sempe C, Bodrug S, Kitada S and Hanada M. . 1996 J. Cell Biochem. 60: 23–32.

  • Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB and Fesik SW. . 1997 Science 275: 983–986.

  • Thompson CB. . 1995 Science 267: 1456–1462.

  • Tokutake N, Miyoshi H, Satoh T, Hatano T and Iwamura H. . 1994 Biochim. Biophys. Acta 1185: 271–278.

  • Tomita F, Tamaoki T, Shirahata K, Kasai M, Morimoto M, Ohkubo S, Mineura K and Ishii S. . 1980 J. Antibiot. (Tokyo) 33: 668–670.

  • Tzung SP, Kim KM, Basanez G, Zimmerberg J, Zhang KYJ and Hockenbery DM. . 1999 Molecular Targets and Cancer Therapeutics: Discovery, Development and Clinical validation. AACR-NCI-EORTIC International conference, 87.

    Google Scholar 

  • Wang J, Liu D, Zhang Z, Shan S, Han X, Srinivasula SM, Croce CM, Alnemri ES and Huang Z. . 2000a Proc. Natl. Acad. Sci. USA 97: 7124–7129.

  • Wang JL, Zhang ZJ, Choksi S, Shan S, Lu Z, Croce CM, Alnemri ES, Korngold R and Huang Z. . 2000b Cancer Res. 60: 1498–1502.

  • Webb A, Cunningham D, Cotter F, Clarke P, di Stefano F, Ross P, Corbo M and Dziewanowska Z. . 1997 Lancet 349: 1137–1141.

  • Yin XM, Oltvai ZN and Korsmeyer SJ. . 1994 Nature 369: 321–323.

  • Yu N, Aramini JM, Germann MW and Huang Z. . 2000 Tetrahedron Lett 41: 6993–6996.

  • Zha H, Aime-Sempe C, Sato T and Reed JC. . 1996 J. Biol. Chem. 271: 7440–7444.

Download references

Acknowledgements

This paper was adapted from an article entitled ‘Small molecule inhibitors of Bcl-2 function: Modulators of apoptosis and promising anticancer agents' published in Current Opinion in Drug Discovery & Development 3(5), 2000 by ®PharmaPress Ltd, London, UK. I thank all former and current members of my laboratory who have contributed to the Bcl-2 inhibitor project as cited in references and Dr Dongxiang Liu for help in preparing the manuscript. I also thank my colleagues Drs Carlo M Croce, Emad S Alnemri, Robert Korngold, Markus W Germann, Robert L Capizzi, Renato Baserga, Philip Tsichlis and Bruno Calabretta at Kimmel Cancer Center of Thomas Jefferson University for their collaboration and discussion. This work was supported by grants from the National Institutes of Health, the American Cancer Society and the Sidney Kimmel Foundation for Cancer Research.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, Z. Bcl-2 family proteins as targets for anticancer drug design. Oncogene 19, 6627–6631 (2000). https://doi.org/10.1038/sj.onc.1204087

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204087

Keywords

This article is cited by

Search

Quick links