Abstract
4849
Breast and ovarian cancers account for 21% of all women cancer deaths in the US in 2006. While early detection and better treatment options might have improved the chances of surviving these two types of cancer, many patients still suffer from poor responses to chemotherapy and recurrences. It is imperative to search for new agents that may have potential therapeutic activity against the aggressive, metastatic phenotypes. In the current study, we have evaluated the anti-cancer potential of triptolide, which is a compound isolated from the Chinese herb Trypterygium wilfordii hook f, using a panel of breast and ovarian cancer cell lines. Triptolide exhibited potent cytotoxic effects in MCF-7, MCF-7HER2, MDA-MB-231, JIMT-1, OVCAR-3 and SKOV-3 cancer cells, with IC50 values ranging from 2 - 20 nM as determined by the MTT assay after 72 h of drug exposure. These IC50 values were at least 100-fold lower than those of doxorubicin and gemcitabine, which are two drugs commonly used in breast and ovarian cancer therapy. Similar concentration range of triptolide was also capable of inhibiting anchorage-independent growth of MCF-7 and JIMT-1 breast cancer cells, as reflected by the reduced clonogenicity in soft agar upon exposure to triptolide for 12 - 21 days. DNA fragmentation was observed in cancer cells treated with triptolide in a time-dependent manner, suggesting the ability of triptolide to induce apoptosis. To investigate whether triptolide was effective in reducing the metastatic potential of the cancer cells, we have used the in vitro matrigel invasion assay for evaluation. A 24-h exposure to triptolide at sub-lethal concentrations reduced the ability of MDA-MB-231 breast cancer cells to invade the matrigel by 35% as compared to the untreated cells. At the molecular level, triptolide treatment reduced the expression of phosphorylated Akt (p-Akt-Ser 473) and the secretion of uPA in MDA-MB-231 cells, both of which have been implied to play important roles in the metastasis of breast cancer cells. Taken together, our results demonstrated the therapeutic potential of triptolide in the treatment of breast and ovarian cancers, and in particular, triptolide was effective against the metastatic phenotype.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA