The Potential Application Of Docetaxel In Combiantion With Celastrol For The Treatment Of Prostate Cancer

Taxol represents a family of anticancer drug that is a widely used in clinic.Docetaxel is the second-generation product of this family, as a second-line anti-cancerdrug for the treatment of prostate cancer. Studies have shown that NF-κB presentsconstitutively high expression in prostate cancer cells, which is further activated upondocetaxel treatment, resulting in tumor resistance to this drug. Therefore, to findeffective ways to overcome docetaxel-induced activation of endogenous NF-κB willhelp enhancing its apoptotic effect, which is expected to enhance its clinical efficacy. Ithas been shown that celastrol, a major component of traditional Chinese medicineTripterygium, inhibits the proteasomal activity, resulting in the accumulation of NF-κBinhibitor of IκB-α, thereby inhibiting NF-κB pathway. In view of this, the current studyis aimed to explore whether celastrtol in combination with docetaxel can reducedocetaxel-induced NF-κB activation thereby enhance the apoptotic effect in prostatecancer cells.In this study, human prostate cancer PC-3cells were used as a model. Dose-dependent inhibition on prostate cancer cell proliferation by celastrol or docetaxel asmonotherapy was determined by MTT assay. Cell death induced by the two drugscombination was analyzed by Trypan blue staining. The combination index (CI) wasdetermined through Chou calculation. Celastrol in combination with docetaxel show-edsynergistic effects when the mortality rate less than60%. Flow cytometry analysisshowed that the apoptotic population was significantly increased in combination ther-apy compared with monotherapy. Consistently, more pronounced apoptoticmorphological changes were observed in combination therapy compared with mono-therapy. Real-time PCR and Western blotting results showed that NF-κB/p65expre-ssions at both mRNA and protein levels were decreased by celastrol in combinationwith doccetaxel compared with docetaxel alone. In addition, inhibition on NF-κB/p65translocation from the cytoplasm to the nucleus was shown by celastrol combinationtherapy compared with docetaxel monotherapy. Inhibition on the function of NF-κB bycelastrol combination therapy was further confirmed by the decreased expression ofBcl-2, a target gene of NF-κB. Celastrol treatment caused accumulation of IκB-α in thecytoplasm, which might be related to NF-κB inhibition. The results above indicate thatcelastrol and docetaxel at the lower concentrations have a synergistic effect on cellproliferation inhibition and apoptosis induction in prostate cancer. Celastrol could reduce the function of NF-κB against docetaxel, which might be one of the reasons ofthe synergistic effects.