Therapeutic Enhancement of Verteporfin-mediated Photodynamic Therapy by mTOR Inhibitors

摘要

Photodynamic therapy (PDT) with photosensitizer verteporfin is a clinically approved vascular disrupting modality that is currently in clinical trial for cancer treatment. In this study, we evaluated PDT in combination with either mTORC1 inhibitor rapamycin or mTORC1/C2 dual inhibitor AZD2014 for therapeutic enhancement in SVEC endothelial cells. Verteporfin-PDT alone induced cell apoptosis by activating the intrinsic apoptotic pathway. However, it increased the expression of anti-apoptotic protein MCL-1 and the phosphorylation of S6, a downstream molecule of mTOR signaling. In contrast, mTOR inhibitors rapamycin and AZD2014 did not induce apoptosis in SVEC cells. They suppressed MCL-1 expression and S6 phosphorylation and imposed a potent inhibition on cell proliferation. PDT in combination with mTOR inhibitors activated the intrinsic apoptotic pathway and resulted in increased apoptosis. Combination treatments also led to sustained inhibition of cell proliferation. Although AZD2014 was more effective for cell growth inhibition and PDT enhancement than rapamycin at the higher concentrations examined in the study, both inhibitors effectively enhanced PDT response, suggesting that inhibition of mTORC1 is crucial for PDT enhancement. Our results indicate that mTOR inhibitors mechanistically cooperate with PDT for enhanced cell death and sustained growth inhibition, supporting a combination approach for therapeutic enhancement.