Autophagy inhibition enhances photocytotoxicity of Photosan-II in human colorectal cancer cells

Abstract

Photodynamic therapy (PDT) has emerged as an attractive therapeutic treatment for colorectal cancer because of its accessibility through endoscopy and its ability to selectively target tumors without destroying the anatomical integrity of the colon. We therefore investigated the therapeutic relevance of the interplay between autophagy and apoptosis in Photosan-II (PS-II)-mediated photodynamic therapy (PS-PDT) in in vitro and in vivo models for human colorectal cancer. We observed that PS-PDT-induced dose-dependently triggered apoptosis and autophagy in both SW620 and HCT116 cells. PS-PDT-treated SW620 cells exhibited nuclear condensation and increased levels of cleaved caspase-3, PARP and Bax, which is reminiscent of apoptosis. PS-PDT also induced autophagic vacuoles, double membrane autophagosome structures and the autophagy-related proteins P62, Bcl-2, ATG7 and LC3-II. In addition, the AKT-mTOR pathway was downregulated, while AMPK was upregulated in PS-PDT-treated cells. Inhibiting autophagy using chloroquine or by downregulating ATG7 using shRNA further upregulated apoptosis, suggesting autophagy was probably was protective to PS-PDT-treated tumor cells. In vivo relevance was demonstrated when a combination of chloroquine and PS-PDT significantly reduced the tumor size in a xenograft mice model. Our findings demonstrate that combination therapy using PS-PDT and autophagy inhibitors may be an effective approach to treating colorectal cancer patients.