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Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3

2017; Impact Journals LLC; Volume: 8; Issue: 60 Linguagem: Inglês

10.18632/oncotarget.20924

1949-2553

Vinothkumar Rajamanickam, Heping Zhu, Feng Chen, Xi Chen, Hailun Zheng, Xiaohong Xu, Qianqian Zhang, Peng Zou, Guodong He, Xuanxuan Dai, Xi Yang, Yi Wang, Zhiguo Liu, Guang Liang, Gui-Long Guo,

Genomics, phytochemicals, and oxidative stress

// Vinothkumar Rajamanickam 1 , Heping Zhu 1 , Chen Feng 1 , Xi Chen 1 , Hailun Zheng 1 , Xiaohong Xu 1 , Qianqian Zhang 1, 2 , Peng Zou 1 , Guodong He 1, 3 , Xuanxuan Dai 1, 4 , Xi Yang 1, 5 , Yi Wang 1 , Zhiguo Liu 1 , Guang Liang 1 and Guilong Guo 1, 4 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China 2 Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, P.R. China 3 Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China 4 Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China 5 The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China Correspondence to: Guang Liang, email: wzmcliangguang@163.com Guilong Guo, email: guoguilong930@126.com Keywords: gastric cancer, curcumin analog, reactive oxygen species, ER stress, pSTAT3 Received: June 28, 2017 Accepted: August 27, 2017 Published: September 15, 2017 ABSTRACT Curcumin is a promising active compound from a natural source and is extensively being tested in clinical trials because of its bio-functional properties. However, poor bioavailability has hampered its clinical application. Numerous attempts have been made in our laboratory to discover analogs of curcumin with enhanced bioavailability and superior pharmacological activity. In this study, we have investigated a new series of allylated monocarbonyl analogs of curcumin (MAC) and tested their effect on gastric cancer cells. Our results show six MAC that selectively targeted cancer cell lines to inhibit growth and induce apoptosis. This activity was achieved by generation of reactive oxygen species (ROS) by MAC. We selected one effective MAC (CA10) for further investigation and show that CA10 inhibits cell growth by causing G2/M cell cycle arrest and induction of apoptotic death. CA10 induced ROS generation and subsequent activation of endoplasmic reticulum (ER) stress and inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation, inhibits cancer cell proliferation. These anti-tumor activities of CA10 were confirmed in gastric cancer xenografts. CA10 induced ROS, activated the ER stress pathway and inhibited STAT3 phosphorylation and gastric xenografts tumor growth in mice. Our studies provide experimental evidence that MAC CA10 effectively targets gastric cancer in preclinical models by enhancing ROS and ROS-mediated signaling.