(-)-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 Citations (Scopus)

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

Gossypol
Prostatic Neoplasms
Radiotherapy
Radiation
Neoplasms
Polyphenols
Molecular Targeted Therapy
Apoptosis
Staining and Labeling
Cottonseed Oil
DNA Nucleotidylexotransferase
Ionizing Radiation
Heterografts
Nude Mice
Signal Transduction
Proteins
Cell Death
X-Rays
Hormones

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Xu, L., Yang, D., Wang, S., Tang, W., Liu, M., Davis, M., ... 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.

(-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. / Xu, Liang; Yang, Dajun; Wang, Shaomeng; Tang, Wenhua; Liu, Meilan; Davis, Mary; Chen, Jianyong; Rae, James M.; Lawrence, Theodore; Lippman, Marc E.

In: Molecular Cancer Therapeutics, Vol. 4, No. 2, 01.02.2005, p. 197-205.

Research output: Contribution to journalArticle

Xu, L, Yang, D, Wang, S, Tang, W, Liu, M, Davis, M, Chen, J, Rae, JM, Lawrence, T & Lippman, ME 2005, '(-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer', Molecular Cancer Therapeutics, vol. 4, no. 2, pp. 197-205.
Xu, Liang ; Yang, Dajun ; Wang, Shaomeng ; Tang, Wenhua ; Liu, Meilan ; Davis, Mary ; Chen, Jianyong ; Rae, James M. ; Lawrence, Theodore ; Lippman, Marc E. / (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 2. pp. 197-205.
@article{d412c42ec656411995fbbe67d2eae4b0,
title = "(-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer",
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.",
author = "Liang Xu and Dajun Yang and Shaomeng Wang and Wenhua Tang and Meilan Liu and Mary Davis and Jianyong Chen and Rae, {James M.} and Theodore Lawrence and Lippman, {Marc E}",
year = "2005",
month = "2",
day = "1",
language = "English",
volume = "4",
pages = "197--205",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer

AU - Xu, Liang

AU - Yang, Dajun

AU - Wang, Shaomeng

AU - Tang, Wenhua

AU - Liu, Meilan

AU - Davis, Mary

AU - Chen, Jianyong

AU - Rae, James M.

AU - Lawrence, Theodore

AU - Lippman, Marc E

PY - 2005/2/1

Y1 - 2005/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=20044368078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20044368078&partnerID=8YFLogxK

M3 - Article

C2 - 15713891

AN - SCOPUS:20044368078

VL - 4

SP - 197

EP - 205

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 2

ER -