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

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

doi:10.18632/oncotarget.20924

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.

Highlights

Medicinal herbs have served as an excellent resource for drug design and discovery
Cytotoxic screening of allylated monocarbonyl analogs of curcumin (MAC) on various gastrointestinal cell lines First, we investigated whether allylated MAC alter the viability or have cytotoxic effects on cells in culture
We show that MAC produce a pronounced inhibition of tumor cell growth (Table 1)

Summary

Introduction

Medicinal herbs have served as an excellent resource for drug design and discovery. Curcumin is a naturally occurring hydrophobic polyphenolic compound which is isolated from the rhizome of the traditional herbal plant (Curcuma longa Linn). Despite the biological efficacy and safety profile of curcumin, it has not yet been approved as a therapeutic agent This is because of pharmacokinetic limitations such as extensive metabolism and rapid elimination [6, 7]. We designed and synthesized a series of novel monocarbonyl analogs of curcumin (MAC) by deleting unstable moiety and modifying its substituents at different positions [8, 9]. These alterations have produced promising pharmacokinetic profiles of MAC compared to that of curcumin [8, 9]. The mechanism of the anti-tumor activity of MAC is still not clear

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