title: Screening of mammalian DNA polymerase and topoisomerase inhibitors from Garcinia mangostana L. and analysis of human cancer cell proliferation and apoptosis.
abstract: We purified and identified eight xanthones from mangosteen (Garcinia mangostana L.) and investigated whether these compounds inhibited the activities of mammalian DNA polymerases (Pols) and human DNA topoisomerases (Topos). β-Mangostin was the strongest inhibitor of both mammalian Pols and human Topos among the isolated xanthones, with 50% inhibitory concentration (IC50) values of 6.4-39.6 and 8.5-10 µM, respectively. Thermal transition analysis indicated that β-mangostin did not directly bind to double-stranded DNA, suggesting that this compound directly bound the enzyme protein rather than the DNA substrate. β-Mangostin showed the strongest suppression of human cervical cancer HeLa cell proliferation among the eight compounds tested, with a 50% lethal dose (LD50) of 27.2 µM. This compound halted cell cycle in S phase at 12-h treatment and induced apoptosis. These results suggest that decreased proliferation by β-mangostin may be a result of the inhibition of cellular Pols rather than Topos, and β-mangostin might be an anticancer chemotherapeutic agent.
authors.affiliation: Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Hyogo 651-8586, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Onodera
authors.affiliation: Kobe Pharmaceutical University, Higashinada-ku, Kobe, Hyogo 658-8558, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Takenaka
authors.affiliation: Kobe Pharmaceutical University, Higashinada-ku, Kobe, Hyogo 658-8558, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kozaki
authors.affiliation: Kobe Pharmaceutical University, Higashinada-ku, Kobe, Hyogo 658-8558, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Tanahashi
authors.affiliation: Graduate School of Agriculture, Shinshu University, Minamiminowa-mura, Kamiina-gun, Nagano 399-4598, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002453:Cell Cycle; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry; D004277:DNA, Single-Stranded / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D029762:Garcinia mangostana / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry*; D051381:Rats; D059003:Topoisomerase Inhibitors / Q000737:chemistry*; D044004:Xanthones / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D007211:Indoles; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors; D044004:Xanthones; C007293:DAPI; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D053148:Caspase 3; C021053:mangostin