title: Upregulation of both heme oxygenase-1 and ATPase inhibitory factor 1 renders tumoricidal activity by synthetic flavonoids via depleting cellular ATP.
abstract: Heme oxygenase-1 (HO-1) and ATPase inhibitory factor (ATPIF) 1 is often overexpressed in different types of cancer cells. Chrysin is a naturally-occurring flavonoid with antioxidant potentials, but also known to promote apoptosis. We have synthesized four chrysin derivatives and found compounds 1 and 4 remarkably upregulated the expression of HO-1, a cytoprotective enzyme. A robust expression of ATPIF1 was only seen in compound 4. Upregulation of both proteins triggers cell death in hydrogen peroxide-primed cells. Ten derivatives of compound 4 were synthesized and measured the expression of HO-1 and ATPIF1. Again, upregulation of both proteins by compound 8 killed the cells via apoptosis. To gain a physiological significance, we treated the synthetic flavonoids in colon cancer cells, HT29 and HCT116 cells and confirmed that overexpression of both HO-1 and ATPIF1 was critical for tumor cell death with an impaired mitochondrial energetics. It would provide a strategy for developing selective anti-tumor candidates.
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Phil Jun
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Iljin
authors.initials: I
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Hyoungsu
authors.initials: H
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: ghim@ajou.ac.kr.
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015394:Molecular Structure; D011506:Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects*; D000097795:ATPase Inhibitory Protein
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D005419:Flavonoids; D051547:Heme Oxygenase-1; D006861:Hydrogen Peroxide; D011506:Proteins; D000097795:ATPase Inhibitory Protein; C043561:chrysin
keywords: ATPIF1; Apoptosis; Chrysin derivatives; Energetics; Heme oxygenase