title: The novel anthraquinone derivative IMP1338 induces death of human cancer cells by p53-independent S and G2/M cell cycle arrest.
abstract: To identify novel small molecules that induce selective cancer cell death, we screened a chemical library containing 1040 compounds in HT29 colon cancer and CCD18-Co normal colon cells, using a phenotypic cell-based viability assay system with the Cell Counting Kit-8 (CCK-8). We discovered a novel anthraquinone derivative, N-(4-[{(9,10-dioxo-9,10-dihydro-1-anthracenyl)sulfonyl}amino]phenyl)-N-methylacetamide (IMP1338), which was cytotoxic against the human colon cancer cells tested. The MTT cell viability assay showed that treatment with IMP1338 selectively inhibited HCT116, HCT116 p53(-/-), HT29, and A549 cancer cell proliferation compared to that of Beas2B normal epithelial cells. To elucidate the cellular mechanism underlying the cytotoxicity of IMP1338, we examined the effect of IMP1338 on the cell cycle distribution and death of cancer cells. IMP1338 treatment significantly arrested the cell cycle at S and G2/M phases by DNA damage and led to apoptotic cell death, which was determined using FACS analysis with Annexin V/PI double staining. Furthermore, IMP1338 increased caspase-3 cleavage in wild-type p53, p53 knockout HCT116, and HT29 cells as determined using immunoblotting. In addition, IMP1338 markedly induced the phosphorylation of histone H2AX and Chk1 in both cell lines while the combination of 5-fluorouracil (5-FU) and radiation inhibited the viability of HCT116, HCT116 p53(-/-), and HT29 cells compared to 5-FU or radiation alone. Our findings indicated that IMP1338 induced p53-independent cell death through S and G2/M phase arrest as well as DNA damage. These results provide a basis for future investigations assessing the promising anticancer properties of IMP1338.
authors.affiliation: Department of Medicinal Chemistry, Jungwon University, 85 Munmuro, Goesan 28024, South Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowonro Nowongu, Seoul 01812, South Korea.
authors.forename: Hwani
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowonro Nowongu, Seoul 01812, South Korea.
authors.forename: A-Rang
authors.initials: AR
authors.lastname: Son
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowonro Nowongu, Seoul 01812, South Korea.
authors.forename: Bitna
authors.initials: B
authors.lastname: Seo
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowonro Nowongu, Seoul 01812, South Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowonro Nowongu, Seoul 01812, South Korea. Electronic address: immu@kcch.re.kr.
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowonro Nowongu, Seoul 01812, South Korea. Electronic address: ahnjy@kirams.re.kr.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ahn
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D011836:Radiation Tolerance / Q000187:drug effects; D016196:S Phase / Q000187:drug effects*; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; C000613086:IMP1338; D054852:Small Molecule Libraries; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53
keywords: Anthraquinone derivative; Cell cycle arrest; Chemosensitizer; Radiosensitizer; Selective cytotoxicity