Inhibition of topoisomerase I activity and efflux drug transporters' expression by xanthohumol. from hops.
Xanthohumol (XN) and its related compounds were evaluated for their cytotoxicity against four different human cancer cell lines, A549 (lung), SK-OV-3 (ovarian), SK-MEL-2 (melanoma), and HCT-15 (colon) using a sulforhodamine B assay. XN showed the most active cytotoxicity against the human cancer cell lines. Isoxanthohumol, 8-prenylnaringenin, and xanthohumol 4'-O-beta-D-glucopyranoside showed comparable cytotoxicity and (2S)-5-methoxy-8-prenylnaringenin 7-O-beta-D-glucopyranoside was the least cytotoxic compound. The anticancer properties of XN, the most active cytotoxic compound, were further investigated. XN showed an inhibitory effect on the activity of DNA topoisomerase I (topo I), which was measured from the relaxation of supercoiled DNA. The inhibition of topo I by XN might explain the cytotoxicity against the human cancer cell lines. Moreover, the expression of the drug efflux genes was investigated to predict the drug resistance. XN clearly decreased the mRNA levels of ABCB1 (MDR1), ABCC1 (MRP1), ABCC2 (MRP2), and ABCC3 (MRP3). These results suggest that XN has anticancer properties by inhibiting the topo I activity and it might be used in conjunction with other anticancer chemotherapeutic agents to reduce the drug resistance inhibiting the efflux drug transporters.
Lee
Sung Ho
SH
College of Pharmacy, Chonnam National University, Gwangju 500-757, Korea.
Kim
Hyun Jung
HJ
Lee
Jung Sun
JS
Lee
Ik-Soo
IS
Kang
Bok Yun
BY
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D011427:Propiophenones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D059004:Topoisomerase I Inhibitors
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D051547:Heme Oxygenase-1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011427:Propiophenones; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C104536:xanthohumol; C421109:multidrug resistance-associated protein 1