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

// Yan-Feng Huang 1 , Da-Jian Zhu 2 , Xiao-Wu Chen 3 , Qi-Kang Chen 2 , Zhen-Tao Luo 3 , Chang-Chun Liu 3 , Guo-Xin Wang 3 , Wei-Jie Zhang 3 and Nv-Zhu Liao 2 1 Department of Traditional Chinese Medicine, Shunde Hospital of Southern Medical University, Guangdong 528300, China 2 Department of Gastrointestinal Surgery, Shunde Women and Children’s Hospital Affiliated to Jinan University, Guangdong 528300, China 3 Department of Gastrointestinal Surgery, Shunde Hospital of Southern Medical University, Guangdong 528300, China Correspondence to: Da-Jian Zhu, email: zhudajian2016@126.com Keywords: curcumin, colorectal cancer, irinotecan, ROS, ER stress Received: May 13, 2016 Accepted: February 27, 2017 Published: April 04, 2017 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 Ca 2+ 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.