Biological mechanisms of action of novel C-10 non-acetal trioxane dimers in prostate cancer cell lines

The mechanisms of action of three C-10 non-acetal trioxane dimers (TDs) were examined in human (LNCaP) and mouse (TRAMP-C1A and -C2H) prostate cancer cell lines. 1 (AJM3/23), 2 (GHP-TM-III-07w), and 3 (GHP-KB-06) inhibited cell growth with 3 being the most potent in C1A (GI(50) = 18.0 nM), C2H (GI(50) = 17.0 nM), and LNCaP (GI(50) = 17.9 nM) cells. In comparison to a standard cytotoxic agent such as doxorubicin (GI(50) = 45.3 nM), 3 (GI(50) = 17.9 nM) inhibited LNCaP cell growth more potently. TDs induced G(0)/G(1) cell cycle arrest in LNCaP cells and decreased cells in the S phase. These changes correlated with modulation of G(1) phase cell cycle proteins including decreased cyclin D1, cyclin E, and cdk2 and increased p21(waf1) and p27(Kip1). TDs also promoted apoptosis in LNCaP cells with increased expression of proapoptotic bax. These results demonstrate that TDs are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.