title: Inhibition of multidrug resistance of cancer cells by natural diterpenes, triterpenes and carotenoids.
abstract: The multidrug resistance (MDR) proteins are member of the ATP-binding cassette superfamily and are present in a majority of human tumors. Their activity is a crucial factor leading to therapeutic failure. It is likely that compounds which inhibit the function of the MDR-efflux proteins such as MDR1 will improve the cytotoxic action of anticancer chemotherapy. Therefore, a search for MDR reversing compounds was conducted among three classes of plant derived compounds such as diterpenes, triterpenes and carotenoids in a hope to find inhibitors without adverse effects in these natural compounds. The inhibition of efflux activity was determined by measuring the accumulation of substrate analogues such as rhodamine in tumor cells in the presence of potential inhibitors. Thus we determined the effect of structurally unrelated diterpenes, triterpenes and carotenoids on reversal of multidrug resistance in MDR-1 gene-transfected L1210 mouse lymphoma cells and MDR mediated multidrug resistance of human breast cancer cells MDA-MB-231 (HTB-26) and MCF-7. The majority of diterpenes, cycloartane triterpenes and carotenoids isolated from vegetables and medicinal plants were able to enhance rhodamine 123 accumulations of MDR-cells. Synergistic interaction was found between epirubicine and resistance modifier terpenoids in vitro. It is supposed that these MDR modulators bind into transmembrane domains and the action of ABC transporters is inhibited by induced conformational changes.
authors.affiliation: Institute of Medical Microbiology and Immunology, University of Szeged, H-6720 Szeged, Dóm tér 10, Hungary. molnarj@comser.szote.u-szeged.hu
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.forename: Nóra
authors.initials: N
authors.lastname: Gyémánt
authors.forename: Masaru
authors.initials: M
authors.lastname: Tanaka
authors.forename: Judith
authors.initials: J
authors.lastname: Hohmann
authors.forename: Elke
authors.initials: E
authors.lastname: Bergmann-Leitner
authors.forename: Péter
authors.initials: P
authors.lastname: Molnár
authors.forename: Joseph
authors.initials: J
authors.lastname: Deli
authors.forename: Remigijus
authors.initials: R
authors.lastname: Didiziapetris
authors.forename: Maria José Umbelino
authors.initials: MJ
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002338:Carotenoids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D014315:Triterpenes; D002338:Carotenoids