title: CHNQ, a novel 2-Chloro-1,4-naphthoquinone derivative of quercetin, induces oxidative stress and autophagy both in vitro and in vivo.
abstract: Quercetin (Qc) shows strong antitumor effects but has limited clinical application due to poor water solubility and bioavailability. In a screening of novel semi-synthetic derivatives of Qc, 3,7-dihydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxyphenyl]-5-hydroxychromen-4-one (CHNQ) could ameliorate acetic acid induced acute colitis in vivo more efficiently than Qc. Since inflammation contributes to colorectal cancer (CRC), we have hypothesized that CHNQ may have anti-cancer effects. Using CRC cell lines HCT-116 and HT-29, we report that CHNQ was three-fold more cytotoxic than Qc along with a robust induction of apoptosis. As expected from naphthoquinones such as CHNQ, a strong induction of oxidative stress was observed. This was accompanied by reactive oxygen species (ROS) induced autophagy marked by a dramatic increase in the lipidation of LC3, decreased activation of Akt/PKB, acidic vesicle accumulation and puncta formation in HCT-116 cells treated with CHNQ. Interestingly, an incomplete autophagy was observed in HT-29 cells where CHNQ treatment led to LC3 lipidation, but not the formation of acidic vacuoles. CHNQ-induced cytotoxicity, ROS formation and autophagy were also detected in vivo in Saccharomyces cerevisiae strain RDKY3615 (WinstonS288C background). Overall, we propose that CHNQ can induce cancer cell death through the induction of oxidative stress, and may be examined further as a potential chemotherapeutic drug.
authors.affiliation: Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Enayat
authors.affiliation: Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey.
authors.forename: M
authors.initials: M
authors.lastname: Şeyma Ceyhan
authors.affiliation: Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey.
authors.forename: Betül
authors.initials: B
authors.lastname: Taşkoparan
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04, Bratislava, Slovakia.
authors.forename: Milan
authors.initials: M
authors.lastname: Stefek
authors.affiliation: Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey. Electronic address: banerjee@metu.edu.tr.
authors.forename: Sreeparna
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D011794:Quercetin; D051057:Proto-Oncogene Proteins c-akt
keywords: Autophagy; CHNQ; Colon cancer; Oxidative stress; Quercetin