Endoplasmic reticulum-targeting photosensitizer Hypericin confers chemo-sensitization towards oxaliplatin through inducing pro-death autophagy.

Abstract

Hypericin is an endoplasmic reticulum (ER)-located photosensitizer, which causes oxidative damage to ER during photodynamic therapy (PDT). Hypericin-mediated PDT (HY-PDT) has been confirmed to enhance chemo-sensitivity of oxaliplatin (L-OHP) in colon cancer cells. The present study reveals that autophagy plays a key role in chemosensitization during HY-PDT. We proved pro-death autophagy was required for sensitization and HY-PDT/L-OHP antitumor synergism. High dosage of HY-PDT induced autophagic cell death; while low dose of HY-PDT predominantly triggered protective autophagy and promoted cell proliferation. Low dose of HY-PDT reduced the cytotoxicity of L-OHP in oxaliplatin-resistant colon cancer cells. Different level of autophagy therefore contributed to the opposite effect of HY-PDT on cell fate and chemo-sensitivity. Furthermore, we revealed the role of CHOP as a regulator connecting pro-survival and pro-death autophagy under ER damage. High dose of HY-PDT induced massive ROS generation and severe ER stress, which then led to induction of CHOP. CHOP thereby activated CHOP/TRIB3/Akt/mTOR cascade and triggered autophagic cell death. Additionally, when apoptotic pathway was blocked, cells treated with high dose of HY-PDT preferentially underwent death through autophagic pathway. On the other hand, suppression of autophagy made cells more vulnerable to apoptosis under low dose of HY-PDT. These results provided new evidences for the clinical application of ER-targeting PDT in modifying chemosensitivity of colorectal cancer therapy.

• Authors: Shengchao Lin, Liyan Yang, Haiyang Shi, Wenpei Du, Yingxue Qi, Cen Qiu, Xin Liang, Weibin Shi, Jianwen Liu
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 87 Pg. 54-68 (06 2017) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 28392376 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier Ltd.

Chemical References

• Anthracenes
• Organoplatinum Compounds
• Photosensitizing Agents
• Reactive Oxygen Species
• Oxaliplatin
• Perylene
• hypericin

Topics

• Animals
• Anthracenes
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Endoplasmic Reticulum (drug effects, metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Female
• HCT116 Cells
• Humans
• Mice
• Organoplatinum Compounds (pharmacology)
• Oxaliplatin
• Perylene (analogs & derivatives, pharmacology)
• Photosensitizing Agents (pharmacology)
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays