Background
Docetaxel is a first-line treat
ment choice in castration-resistant prostate cancer (CRPC). However, the
manage
ment of CRPC re
mains an i
mportant challenge in oncology. There have been
many reports on the effects of rapa
mycin, which is an inhibitor of the
ma
mmalian target of rapa
mycin (
mTOR), in the treat
ment of carcinogenesis. We assessed the cytotoxic effects of the co
mbination treat
ment of docetaxel and rapa
mycin in prostate cancer cells. Further
more, we exa
mined the relationship between these treat
ments and survivin, which is a
me
mber of the inhibitory apoptosis fa
mily.
Methods
Prostate cancer cells were cultured and treated with docetaxel and rapamycin. The effects on proliferation were evaluated with the MTS assay. In addition, we evaluated the effect on proliferation of the combination treatment induced knockdown of survivin expression by small interfering RNA transfection and docetaxel. Protein expression levels were assayed using western blotting. PC3 cells and xenograft growth in nude mice were used to evaluate the m>in vivom> efficacy of docetaxel and its combination with rapamycin.
Results
m>In vitrom> and m>in vivom>, the combination of rapamycin with docetaxel resulted in a greater inhibition of proliferation than treatment with rapamycin or docetaxel alone. In addition, m>in vitrom> and m>in vivom>, rapamycin decreased basal surviving levels, and cotreatment with docetaxel further decreased these levels. Transfection siRNA against survivin enhanced the cytotoxicity of docetaxel in PC3 cells.
Conclusion
The rapamycin-dependent enhancement of the cytotoxic effects of docetaxel was associated with the downregulation of survivin expression. Our results suggest that the combination of docetaxel and rapamycin is a candidate for the improved treatment of advanced prostate cancer.