3 ',5-dihydroxy-3,4 ',7-trimethoxyflavone-induces ER-stress-associated HCT-116 programmed cell death via redox signaling

초록

Quercetin, a well cognized bioactive flavone possessing great medicinal value, has limited usage. The rapid gastrointestinal digestion of quercetin is also a major obstacle for its clinical implementation due to low bioavailability and poor aqueous solubility. 30,5-dihydroxy-3,40,7-trimethoxyflavone (DTMF), a novel semi-synthetic derivative of quercetin, is known to modulate several biological activities. Therefore, in the present study we examined the cytotoxic mechanism of DTMF in concentration-dependent manner (25, 50, and 100 mu M; 24 h) against HCT-116 human colon carcinoma cells. The cytotoxic potential of DTMF was characterized based on deformed cell morphology, increased ROS accumulation, loss of mitochondrial membrane potential (Delta psi m), increased mitochondrial mass, chromatin condensation, and typical DNA-fragmentation in HCT-116 cells. The results showed that DTMF-induced enhanced ROS production at higher concentration (100 mu M) as evidenced by upregulated expression of ER stress and apoptotic proteins with concomitant increase in PERK, CHOP, and JNK levels, when compared to N-acetyl cysteine (NAC, ROS inhibitor) treated HCT-116 cells, which depicts that DTMF might act as a crucial mediator of apoptosis signaling. Collectively, our results suggest that DTMF stimulates ROS-mediated oxidative stress, which in turn induces PERK-CHOP and JNK pathway of apoptosis to promote HCT-116 cell death. (C) 2017 Elsevier Masson SAS. All rights reserved.

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