Screening of mammalian DNA polymerase and topoisomerase inhibitors from Garcinia mangostana L. and analysis of human cancer cell proliferation and apoptosis

• Published in: International journal of oncology Vol. 48; no. 3; pp. 1145 - 1154
• Main Authors: ONODERA, TAKEFUMI, TAKENAKA, YUKIKO, KOZAKI, SACHIKO, TANAHASHI, TAKAO, MIZUSHINA, YOSHIYUKI
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.03.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Analysis; Animals; anticancer; Antineoplastic Agents - chemistry; Apoptosis; Cancer; Caspase 3 - metabolism; Cattle; Cell Cycle; Cell division; Cell growth; Cell Proliferation; Cervical cancer; Chromatography; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA polymerase inhibition; DNA polymerases; DNA topoisomerase inhibition; DNA, Single-Stranded - chemistry; DNA-Directed DNA Polymerase - metabolism; E coli; Enzymes; Fruits; Garcinia mangostana - chemistry; Genetic aspects; HeLa Cells; Humans; Indoles - chemistry; Inhibitory Concentration 50; Kinases; mangosteen; Medical screening; Metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Nucleic Acid Synthesis Inhibitors - chemistry; Protein binding; Rats; RNA polymerase; Topoisomerase Inhibitors - chemistry; Xanthones - chemistry; β-mangostin; Japan
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2016.3321

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 topoi-somerases (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.