Submitted to: Clinical Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/16/2007
Publication Date: 2/15/2008
Citation: Hu, H., Li, G., Wang, L., Watts, J.J., Combs, G.F., Lu, J. 2008. Methylseleninic Acid Enhances Taxane Drug Efficacy against Human Prostate Cancer and Down-Regulates ntiapoptotic roteins Bcl-XL and Survivin. Clinical Cancer Research. 14(4):1150-1158. Interpretive Summary: Because we had previously found methylseleninic acid (MSeA) to sensitize hormone-refractory prostate cancer (HRPCa) cells to programmed cell death the plant metabolite taxol, we undertook this study to determine the applicability of this effect for taxane drugs in vitro, to determine whether the efficacy of taxol could be enhanced in vivo by MSeA; and to determine the molecular targets of the effect. We used two human prostate cancer cell lines to evaluate the in vitro apoptosis effects of taxol and related compounds in combination with MSeA, measuring the inhibition of growth of xenografts athymic nude mice. We found the combination of MSeA with taxol exerted a greater than additive effect on programmed cell death in these prostate cancer cells. The use of MSeA increased the taxol-induced growth-inhibition of subcutaneous xenografts by a factor of 4, and decreased the expression of two proteins related to the programmed cell death process. We conclude that MSeA can enhance the efficacy of taxol in part by down-regulating the expression of factors that increase programmed cell death. Thus, MSeA may be useful in improving taxol therapy.
Technical Abstract: PURPOSE: Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (taxol) through enhancing multiple caspases. This study aimed to: 1) determine the general applicability of the sensitization effect for taxane drugs in vitro; 2) establish the in vivo efficacy enhancement of paclitaxel by MSeA; and 3) investigate Bcl-XL and survivin as molecular targets of MSeA to augment apoptosis. EXPERIMENTAL DESIGN: DU145 and PC-3 HRPCa cell lines were used to evaluate the in vitro apoptosis effects of paclitaxel, docetaxel and their combination with MSeA and molecular mechanisms. DU145 xenograft growth in athymic nude mice was used to evaluate the in vivo efficacy of paclitaxel and its combination with MSeA. The tumor samples were used to examine Bcl-XL and survivin protein abundance. RESULTS: MSeA combination with paclitaxel or docetaxel exerted a greater than additive apoptosis effect on DU145 and PC-3 cells. In the nude mice, paclitaxel and MSeA combination inhibited growth of DU145 subcutaneous xenograft with equivalent efficacy of a 4-time higher dose of paclitaxel alone. MSeA decreased the basal and paclitaxel-induced expressions of Bcl-XL and survivin in vitro and in vivo. Ectopic expression of Bcl-XL or survivin attenuated MSeA/paclitaxel-induced apoptosis. CONCLUSIONS: MSeA enhanced the efficacy of paclitaxel against HRPCa in vitro and in vivo, at least in part by down-regulating the basal and paclitaxel-induced expression of Bcl-XL and survivin to increase caspase-mediated apoptosis. MSeA may be a novel agent to improve taxane combination therapy.