title: 3',5-dihydroxy-3,4',7-trimethoxyflavone-induces ER-stress-associated HCT-116 programmed cell death via redox signaling.
abstract: 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. 3',5-dihydroxy-3,4',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 100μM; 24h) 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 (ΔѰm), 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 (100μM) 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.
authors.affiliation: Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea.
authors.forename: Mahendra Pal
authors.initials: MP
authors.lastname: Singh
authors.affiliation: Metalloenzyme Research Group and Department of Integrative Plant Science, Chung-Ang University, Anseong 456-756, Republic of Korea.
authors.forename: Jaehong
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea. Electronic address: sckang@daegu.ac.kr.
authors.forename: Sun Chul
authors.initials: SC
authors.lastname: Kang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C000616098:3',5-dihydroxy-3,4',7-trimethoxyflavone; D000975:Antioxidants; D047309:Flavones; D017382:Reactive Oxygen Species; D011794:Quercetin; D002118:Calcium; D000111:Acetylcysteine
keywords: Apoptosis; DNA damage; ER stress; Mitochondria; ROS