Cryptotanshinone sensitizes DU145 prostate cancer cells to Fas(APO1/CD95)-mediated apoptosis through Bcl-2 and MAPK regulation

Fas/APO-1/CD95, a member of the tumor necrosis factor (TNF) receptor superfamily, is a potential anti-cancer factor as it can induce apoptosis in tumor cells. However, despite the fact that many cancer cells express Fas on the membrane, some tumors such as prostate cancer display resistance to Fas-induced apoptosis. In these cases, combination therapy using chemotherapeutic agents and Fas may be more suitable than therapy using Fas alone. In the present study, we demonstrate that the apoptosis inhibitory protein, Bcl-2, was highly expressed in response to Fas in DU145 prostate cancer cells, thereby conferring resistance to apoptosis. We have screened a number of naturally occurring products that may overcome this resistance. Here we report that cryptotanshinone, the major tanshinone isolated from Salvia miltiorrhiza Bunge, can suppress Bcl-2 expression and augment Fas sensitivity in DU145 cells. We further show that JNK and p38 MAPK act upstream of Bcl-2 expression in Fas-treated DU145 cells, and that cryptotanshinone significantly blocked activation of these kinases. Moreover, cryptotanshinone sensitized several tumor cells to a broad range of anti-cancer agents. Collectively, our data suggest that cryptotanshinone has therapeutic potential in the treatment of human prostate cancer.