Euphorbiasteroid reverses P-glycoprotein-mediated multi-drug resistance in human sarcoma cell line MES-SA/Dx5.
In this study, we evaluated whether euphorbiasteroid isolated from Euphorbia lathyris has the potential to reverse P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) by using the drug-sensitive human sarcoma cell line MES-SA and its MDR counterpart MES-SA/Dx5. Interestingly, even at low concentrations of euphorbiasteroid (1-3 microM), it efficiently restored the toxicities of anticancer drugs including vinblastine, taxol and doxorubicin in MES-SA/Dx5 cells. Additionally, the computational Bayesian model for predicting potential P-gp substrates or inhibitors revealed that euphorbiasteroid showed 97% probability for substrate likeness having similar molecular features with 50 P-gp substrates. Consistent with this result, the substrate likeness of euphorbiasteroid was also experimentally confirmed by P-gp ATPase activity assay. In conclusion, our finding suggested that euphorbiasteroid could be a transport substrate for P-gp that can effectively inhibit P-gp-mediated drug transport and reverse resistance to anticancer drugs in MES-SA/Dx5 cells.
Choi
Jung Sook
JS
Laboratory of Chemical Genomics, Korea Research Institute of Chemical Technology, Daejeon, Korea.
Kang
Nam Sook
NS
Min
Yong Ki
YK
Kim
Seong Hwan
SH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D001499:Bayes Theorem; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D028481:Euphorbia / Q000737:chemistry*; D005260:Female; D006801:Humans; D008956:Models, Chemical; D010648:Phenylacetates / Q000302:isolation & purification / Q000494:pharmacology*; D012509:Sarcoma / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D010648:Phenylacetates; C551893:euphorbiasteroid