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

Abstract

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 (IC 50 ) 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 (LD 50 ) 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.

Phloroglucinol Benzophenones and Xanthones from the Leaves of Garcinia cowa and Their Nitric Oxide Production and α-Glucosidase Inhibitory Activities

“…It should be noted that xanthones found in G. cowa are mainly 1,3,6,7-tetraoxygenated xanthones containing a C 5 or C 10 side chain at C-2 or C-8. ,,− , In this study, xanthones having longer side chains, C 15 for compounds 3 and 5 and C 20 for compound 4 , were discovered for the first time in the Clusiaceae family. The known compounds were identified as cowanin ( 6 ), cowanol ( 7 ), mangostanin ( 8 ), β-mangostin ( 9 ), cratoxylone ( 10 ), 3,4-dihydrojacareubin ( 11 ), and mangostinone ( 12 ) by comparison of their NMR spectroscopic data with those previously reported.…”

“…1,2,[4][5][6][7][8]11 In this study, xanthones having longer side chains, C 15 for compounds 3 and 5 and C 20 for compound 4, were discovered for the first time in the Clusiaceae family. The known compounds were identified as cowanin (6), 13 cowanol (7), 13 mangostanin (8), 17 βmangostin (9), 13 cratoxylone (10), 18 3,4-dihydrojacareubin (11), 19 and mangostinone (12) 20 by comparison of their NMR spectroscopic data with those reported. Nitric oxide (NO) is a highly reactive species produced in various parts in the body by enzymatic and nonenzymatic pathways.…”

β‐mangostin suppresses human hepatocellular carcinoma cell invasion through inhibition of MMP‐2 and MMP‐9 expression and activating the ERK and JNK pathways

“…Recent studies suggest that β‐mangostin could inhibit the lipopolysaccharide (LPS)‐induced inflammatory response and carrageenan‐induced peritonitis . β‐mangostin also potently suppresses proliferation of human cervical cancer HeLa cells via inhibiting DNA polymerases, halting the cell cycle in the S phase and inducing apoptosis . β‐mangostin also induces G1 cell cycle arrest in human colon cancer DLD‐1 cells .…”

β‐Mangostin inhibits the metastatic power of cervical cancer cells attributing to suppression of JNK2/AP‐1/Snail cascade

“…B. Lee et al, 2010). Comparing to α‐mangostin, β‐mangostin shows antiproliferative activity on cervical cancer cell HeLa by inhibition of DNA polymerase and topoisomerase (Onodera, Takenaka, Kozaki, Tanahashi, & Mizushina, 2016), exhibits cytotoxicity to leukemia cell HL60 by induction of ROS‐mediated mitochondrial apoptosis and G1 arrest (Omer et al, 2017), and suppresses invasiveness of hepatocellular carcinoma cells by inhibition of ERK/JNK‐mediated MMP‐2/9 expression (Huang et al, 2017). In this study, we further demonstrate that β‐mangostin inhibits metastatic power of cervical cancer cells by suppression of integrin/Src signaling and JNK2‐mediated AP‐1/Snail expression.…”