(-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer.
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.
Xu
Liang
L
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, 5301B Medical Science Research Building III, 1500 West Medical Center Drive, Ann Arbor, MI 48109-0640, USA.
Yang
Dajun
D
Wang
Shaomeng
S
Tang
Wenhua
W
Liu
Meilan
M
Davis
Mary
M
Chen
Jianyong
J
Rae
James M
JM
Lawrence
Theodore
T
Lippman
Marc E
ME
D000818:Animals; D017209:Apoptosis; D003131:Combined Modality Therapy; D006072:Gossypol / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; D051020:bcl-X Protein; D006072:Gossypol