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.

p62 manipulation affects chlorin�e6‑mediated photodynamic therapy efficacy in colorectal cancer cell lines

“…PDT studies with porphyrin IX in HCT116 colon cancer cells reported that inhibition of autophagy was effective for PDT antitumor effects (32). In a study of sinoporphyrin sodium mediated PDT and photosan-II mediated PDT applied to human colorectal cancer cells, autophagy inhibition increased the efficacy of PDT (33,34). In our study, overexpression of p62, which plays an important role in autophagy, increased the effect of PDT, conflicting with previously reported studies.…”

Interplay between apoptosis and autophagy in colorectal cancer

“…celecoxib and an antagonist of Bcl-2/Bcl-xL [ 26 ], PI3K/mTOR inhibitor [ 27 ], BRAF inhibitor [ 28 ], niacin and tumor necrosis factor-related apoptosis-inducing ligand [ 29 ], store-operated Ca 2+ entry inhibitor [ 30 ], SN-38/CPT-11 [ 31 ]), other compounds or extracts (e.g. icaritin [ 32 ], tetrandrine [ 33 ], apigenin [ 34 ], purvalanol [ 35 ]), radiation therapy [ 36 ] and photodynamic therapy [ 37 ]. Moreover, endoplasmic reticulum (ER) stress appears to be a crucial intermediate event as inhibition of ER stress has been found to suppress autophagy and subsequently enhance apoptosis in sodium butyrate-treated CRC cells [ 38 ].…”

Actein induces autophagy and apoptosis in human bladder cancer by potentiating ROS/JNK and inhibiting AKT pathways

“…Autophagy is a lysosomal-dependent degradation process induced under various conditions or stresses [ 29 ]. Autophagy is reported as an alternative molecular mechanism by which the cell death is induced [ 30 ].…”