(-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer

Liang Xu, Dajun Yang, Shaomeng Wang, Wenhua Tang, Meilan Liu, Mary Davis, Jianyong Chen, James M. Rae, Theodore Lawrence, Marc E Lippman

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Radioresistance markedly impairs the efficacy of tumor radiotherapy and involves antiapoptotic signal transduction pathways that prevent radiation-induced cell death. The majority of human prostate cancers overexpress the important antiapoptotic proteins Bcl-2 and/or Bcl-xL, which render tumors resistant to radiation therapy. (-)-Gossypol, a natural polyphenol product from cottonseed, has recently been identified as a potent small molecule inhibitor of both Bcl-2 and Bcl-xL. In the current study, we investigated the antitumor activity of (-)-gossypol in prostate cancer and tested our hypothesis that (-)-gossypol may improve prostate cancer's response to radiation by potentiating radiation-induced apoptosis and thus making cancer cells more sensitive to ionizing radiation. Our data show that (-)-gossypol potently enhanced radiation-induced apoptosis and growth inhibition of human prostate cancer PC-3 cells, which have a high level of Bcl-2/Bcl-xL proteins. Our in vivo studies using PC-3 xenograft models in nude mice show that orally given (-)-gossypol significantly enhanced the antitumor activity of X-ray irradiation, leading to tumor regression in the combination therapy. In situ terminal deoxynucleotidyl transferase - mediated nick end labeling staining showed that significantly more apoptotic cells were induced in the tumors treated with (-)-gossypol plus radiation than either treatment alone. Anti-CD31 immunohistochemical staining indicates that (-)-gossypol plus radiation significantly inhibited tumor angiogenesis. Our results show that the natural polyphenol inhibitor of Bcl-2/Bcl-xL, (-)-gossypol, can radiosensitize prostate cancer in vitro and in vivo without augmenting toxicity. (-)-Gossypol may improve the outcome of current prostate cancer radiotherapy and represents a promising novel anticancer regime for molecular targeted therapy of hormone-refractory prostate cancer with Bcl-2/Bcl-xL overexpression.

Original languageEnglish
Pages (from-to)197-205
Number of pages9
JournalMolecular Cancer Therapeutics
Volume4
Issue number2
StatePublished - Feb 1 2005
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Xu, L., Yang, D., Wang, S., Tang, W., Liu, M., Davis, M., Chen, J., Rae, J. M., Lawrence, T., & Lippman, M. E. (2005). (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. Molecular Cancer Therapeutics, 4(2), 197-205.