title: V8, a newly synthetic flavonoid, induces apoptosis through ROS-mediated ER stress pathway in hepatocellular carcinoma.
abstract: Natural flavonoids from plants have been demonstrated to possess promising chemopreventive activities against various diseases. 7-{4-[Bis-(2-hydroxy-ethyl)-amino]-butoxy}-5-hydroxy-8-methoxy-2-phenyl-chromen-4-one (V8), a newly synthesized derivative of wogonin may have antioxidant, antiviral, anti-inflammatory and anti-tumor potentials as wogonin. Based on the recent findings of V8, the anti-tumor activities and fundamental mechanisms by which V8 inhibits growth of hepatocellular carcinoma were further investigated in this study. After the treatment of V8, a significant inhibition of HepG2 cell proliferation was observed in a dose-dependent manner with the IC50 value of 23 μM using MTT assay. The exposure to V8 also resulted in apoptosis induction and an accumulation of ROS and Ca(2+). Meanwhile, a release of cytochrome c (Cyt-c), activation of BH-3 only proteins and Bax, decrease in mitochondrial membrane potential ΔΨ, as well as a suppression of Bcl-2, pro-caspase9 and pro-caspase3 expression were shown. Moreover, knocking down CHOP partly decreased the effect of V8-mediated apoptosis and activation of GRP78, p-PERK, p-eIF2α, ATF4 and CHOP modulated ER stress triggered by V8. In vivo, V8 inhibited the transplanted mice H22 liver carcinomas in a dose-dependent manner. Compared with wogonin, V8 exhibited stronger anti-proliferative effects both in vitro and in vivo. The underlying mechanism of activating PERK-eIF2α-ATF4 pathway by which V8 induces apoptosis was verified once again in vivo. The apoptosis induction via the mitochondrial pathway by modulating the ROS-mediated ER signaling pathway might serve to provide support for further studies of V8 as a possible anticancer drug in the clinical treatment of cancer.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Fanni
authors.initials: F
authors.lastname: Li
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology; D047309:Flavones / Q000138:chemical synthesis / Q000494:pharmacology*; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000592659:7-(4-(bis-(2-hydroxyethyl)amino)butoxy)-5-hydroxy-8-methoxy-2-phenylchromen-4-one; D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D044950:Flavanones; D047309:Flavones; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; C085514:wogonin