title: Curcumin enhances the effects of irinotecan on colorectal cancer cells through the generation of reactive oxygen species and activation of the endoplasmic reticulum stress pathway.
abstract: Although initially effective against metastatic colorectal cancer (CRC), irinotecan-based chemotherapy leads to resistance and adverse toxicity. Curcumin is well known for its anti-cancer effects in many cancers, including CRC. Here, we describe reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress as important mechanisms by which curcumin enhances irinotecan's effects on CRC cells. CRC cell lines were treated with curcumin and/or irinotecan for 24 h, and then evaluated using cell proliferation assays, cell apoptosis assays, cell cycle analysis, intracellular Ca2+ measurements, ROS measurements and immunoblotting for key ER stress-related proteins. We found that cell viability was inhibited and apoptosis was increased, accompanied by ROS generation and ER stress activation in CRC cells treated with curcumin alone or in combination with irinotecan. Blocking ROS production attenuated the expression of two markers of ER stress: binding of immunoglobulin protein (BIP) and CCAAT/enhancer-binding protein homologous protein (CHOP). Blocking CHOP expression using RNA interference also inhibited ROS generation. These results demonstrated that curcumin could enhance the effects of irinotecan on CRC cells by inhibiting cell viability and inducing cell cycle arrest and apoptosis, and that these effects may be mediated, in part, by ROS generation and activation of the ER stress pathway.
authors.affiliation: Department of Traditional Chinese Medicine, Shunde Hospital of Southern Medical University, Guangdong 528300, China.
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Huang
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Women and Children's Hospital Affiliated to Jinan University, Guangdong 528300, China.
authors.forename: Da-Jian
authors.initials: DJ
authors.lastname: Zhu
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Hospital of Southern Medical University, Guangdong 528300, China.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Women and Children's Hospital Affiliated to Jinan University, Guangdong 528300, China.
authors.forename: Qi-Kang
authors.initials: QK
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Hospital of Southern Medical University, Guangdong 528300, China.
authors.forename: Zhen-Tao
authors.initials: ZT
authors.lastname: Luo
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Hospital of Southern Medical University, Guangdong 528300, China.
authors.forename: Chang-Chun
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Hospital of Southern Medical University, Guangdong 528300, China.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Hospital of Southern Medical University, Guangdong 528300, China.
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: Department of Gastrointestinal Surgery, Shunde Women and Children's Hospital Affiliated to Jinan University, Guangdong 528300, China.
authors.forename: Nv-Zhu
authors.initials: NZ
authors.lastname: Liao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003474:Curcumin / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D000077146:Irinotecan; D003474:Curcumin; D002118:Calcium; D002166:Camptothecin
keywords: ER stress; ROS; colorectal cancer; curcumin; irinotecan