title: Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition.
abstract: P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds' effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer.
authors.affiliation: Institute of Pharmacognosy, University of Szeged, 6720 Szeged, Hungary. hunyadi.a@pharm.u-szeged.hu.|Interdisciplinary Centre for Natural Products, University of Szeged, Eötvös str. 6, 6720 Szeged, Hungary. hunyadi.a@pharm.u-szeged.hu.
authors.forename: Attila
authors.initials: A
authors.lastname: Hunyadi
authors.affiliation: Institute of Pharmacognosy, University of Szeged, 6720 Szeged, Hungary. csjoco88@gmail.com.
authors.forename: József
authors.initials: J
authors.lastname: Csábi
authors.affiliation: Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm sq. 9, 6720 Szeged, Hungary. anasfmartins@gmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Martins
authors.affiliation: Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm sq. 9, 6720 Szeged, Hungary. molnar.jozsef@med.u-szeged.hu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.affiliation: NMR Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért Sq. 4, H-1111 Budapest, Hungary. balazs_attila_gyorgy@ymail.com.
authors.forename: Attila
authors.initials: A
authors.lastname: Balázs
authors.affiliation: NMR Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért Sq. 4, H-1111 Budapest, Hungary. drtothgabor@t-online.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Tóth
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004148:Dioxolanes / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D026461:Ecdysteroids / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004148:Dioxolanes; D026461:Ecdysteroids; D004317:Doxorubicin
keywords: ABCB1 efflux transporter; cancer; chemo-sensitization; combination therapy; ecdysteroid metabolite; multi-drug resistance; poststerone acetonide