title: 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.
authors.affiliation: General Surgery Department of Second Xiangya Hospital, Central South University, Changsha, HN, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiong
authors.affiliation: General Surgery Department of Second Xiangya Hospital, Central South University, Changsha, HN, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: General Surgery Department of Second Xiangya Hospital, Central South University, Changsha, HN, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Ouyang
authors.affiliation: China State Key Laboratory for Powder Metallurgy, Central South University, Changsha, HN, China.
authors.forename: Liangwu
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, HN, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Physics, University of Texas at Arlington, Arlington, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: General Surgery Department of Second Xiangya Hospital, Central South University, Changsha, HN, China.
authors.forename: Xiongying
authors.initials: X
authors.lastname: Miao
authors.affiliation: General Surgery Department of Second Xiangya Hospital, Central South University, Changsha, HN, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; D017319:Photosensitizing Agents; D002738:Chloroquine
keywords: Photosan-II; apoptosis; autophagy; colorectal cancer; photodynamic therapy