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.
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Wenhua
authors.initials: W
authors.lastname: Tang
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
authors.forename: Mary
authors.initials: M
authors.lastname: Davis
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Theodore
authors.initials: T
authors.lastname: Lawrence
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lippman
mesh_terms: 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
chemical_list: 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