Combination treatment with naftopidil increases the efficacy of radiotherapy in PC-3 human prostate cancer cells.

PURPOSE

Clinically, radiotherapy (RT) often leads to the development of prostate cancer (PCa) resistance because of protective responses in cancer cells. One of the mechanisms includes the upregulation of RT-induced antioxidant enzymes. Thus, combination therapy with RT and certain pharmaceutical drugs targeting antioxidant enzymes may be ideal for increasing the efficacy of RT with minimum side effects. Naftopidil is a subtype-selective α-adrenoceptor antagonist used for the treatment of benign prostatic hyperplasia (BPH). In our drug repositioning study, naftopidil showed not only unique growth-inhibitory effects but also AKT phosphorylation-inhibitory effects in PC-3 human PCa cells. Here, we examined the efficacy of additive naftopidil treatment in combination with RT in PC-3 cells.

METHODS

The effects of combination therapy with RT plus naftopidil were analyzed using an animal model of PC-3 xenografts in BALB/c nude mice. The expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was evaluated by western blotting.

RESULTS

Combination therapy with RT plus naftopidil induced a more efficacious delay in PC-3 xenograft tumor growth as compared with monotherapy with naftopidil or RT. In PC-3 tumors, combination therapy with RT plus naftopidil suppressed the upregulation of RT-induced MnSOD expression. In vitro, neither AKT inhibitor IV nor naftopidil directly altered MnSOD expression. Upregulation of RT-induced MnSOD expression was markedly suppressed by combination treatment with RT plus AKT inhibitor IV or naftopidil.

CONCLUSIONS

These results suggest that additive naftopidil treatment in combination with RT may increase the efficacy of RT for the treatment of PCa.