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

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.

Cyclohexanone curcumin analogs inhibit the progression of castration‐resistant prostate cancer in vitro and in vivo

“…18 Replacement of the β-diketone moiety of curcumin with monocarbonyl provides promising pharmacokinetic profiles, improves solubility and stability and enhances selective biological activities. 19 In our previous study, we found that three of the synthetic cyclohexanone curcumin analogs, including analogs 2A, 2F and 2J, showed higher multidrug resistance-reversal properties than that of curcumin. 10 Another previous study reported that cyclohexanone curcumin analogs exerted a greater level of potency in inducing cell death and inhibiting nuclear factor kappa B (NF-κB) activity in prostate cancer cells than that of curcumin.…”

“…The high reactive potential in pH values above 6.5 and the specific substrate for the reductase of β‐diketone moiety resulted in the unstable condition of curcumin both in vitro and in vivo . Replacement of the β‐diketone moiety of curcumin with monocarbonyl provides promising pharmacokinetic profiles, improves solubility and stability and enhances selective biological activities . In our previous study, we found that three of the synthetic cyclohexanone curcumin analogs, including analogs 2A, 2F and 2J, showed higher multidrug resistance‐reversal properties than that of curcumin .…”

The Curcumin Analogue, MS13 (1,5-Bis(4-hydroxy-3- methoxyphenyl)-1,4-pentadiene-3-one), Inhibits Cell Proliferation and Induces Apoptosis in Primary and Metastatic Human Colon Cancer Cells

“…It was reported that DAPs demonstrated anti-cancer effect through induction of apoptosis in various human colon cancer cell lines involving activation of caspase-3 [ 28 , 39 , 114 , 115 ] and down-regulation of anti-apoptotic Bcl-2 protein [ 116 , 117 ] even at a very low concentration between the range of 2.5–6.0 µM [ 45 , 117 ]. Another DAP, 1,5-bis (2-metoxyphenyl)-1,4-pentadiene-3-one (B63) was shown to induce apoptosis in human colon cancer cells via the mitochondrial apoptotic pathway which includes down-regulation of mitochondrial complexes, up-regulation of pro-apoptotic proteins-Bad and Bim, activation of caspase-3, PARP cleavage and cytochrome c release [ 119 ]. Induction of apoptosis by B63 is dependent on the accumulation of ROS leading to ER stress which then caused mitochondrial disfunction [ 118 ].…”

“…Induction of apoptosis by B63 is dependent on the accumulation of ROS leading to ER stress which then caused mitochondrial disfunction [ 118 ]. The down-regulation of the mitochondrial complexes (I-IV) [ 118 ] and inhibition of signal transducer and activator of transcription 3 (STAT3) were also observed in in vivo study of a tumor xenograft derived from athymic nude mice which exhibited greater anti-tumor effect compared to curcumin [ 119 , 120 ]. In addition, Yoshida et al (2018) reported that GO-Y022, a DAP with a similar structure to MS13, was able to suppress gastric tumor growth in transgenic mice (K19-Wnt/C2mE), inhibit phosphorylation of STAT3 without hepatic and renal toxicity, retain localized in tumor areas, as well as exhibit better pharmacokinetic profiles than curcumin [ 44 ] when ingested orally [ 66 ].…”

Cadmium induces cell centrosome amplification via reactive oxygen species as well as endoplasmic reticulum stress pathway

“…Centrosome amplification is often seen in arrested cells (Durcan et al, 2008;Steere et al, 2011). There is also evidence that ER stress can caused cell-cycle arrest (Heo, Kim, Hwang, Kang, & Choi, 2018;Rajamanickam et al, 2017;Q. Wang, Yuan, et al, 2018).…”