Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells.
Interest in exploiting traditional medicines for prevention or treatment of cancer is increasing. Extracts from the herb Tripterygium wilfordii hook F have been used in China for centuries to treat immune-related disorders. Recently it was reported that triptolide (PG490), a purified compound from Tripterygium, possessed antitumor properties and induced apoptosis by p53-independent mechanisms in a variety of malignant cell lines. This property of triptolide attracted our attention because we have found that primary cultures of human prostatic epithelial cells derived from normal tissues and adenocarcinomas are in general extremely resistant to apoptosis. Furthermore, the function of wild-type p53 is impaired in these cells such that drugs that require p53 activity to induce cell death are ineffective. Therefore, the properties of triptolide and the recent approval of its water-soluble form (PG490-88) for entry into Phase I clinical trials suggested that this drug was a promising candidate to test for antitumor activity against prostate cells. Experiments presented here demonstrated that triptolide had dose-dependent effects on both normal and cancer-derived primary cultures of human prostatic epithelial cells. Low concentrations of triptolide inhibited cell proliferation and induced a senescence-like phenotype. Higher concentrations of triptolide induced apoptosis that was unexpectedly associated with nuclear accumulation of p53. Paradoxically, levels of the p53 target genes, p21(WAF1/CIP1) and hdm-2, were reduced, as was bcl-2. Our preclinical studies suggest that triptolide might be an effective preventive as well as therapeutic agent against prostate cancer and that triptolide may activate a functional p53 pathway in prostate cells.
Kiviharju
Taija M
TM
Department of Urology, Stanford University School of Medicine, Stanford, California 94305-5118, USA.
Lecane
Philip S
PS
Sellers
Robert G
RG
Peehl
Donna M
DM
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects; D004852:Epoxy Compounds; D006801:Humans; D015151:Immunoblotting; D008297:Male; D009687:Nuclear Proteins; D010616:Phenanthrenes; D010641:Phenotype; D011467:Prostate / Q000166:cytology / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004224:Diterpenes; D004852:Epoxy Compounds; D009687:Nuclear Proteins; D010616:Phenanthrenes; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C001899:triptolide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D001616:beta-Galactosidase