title: Anticancer and multidrug resistance-reversal effects of solanidine analogs synthetized from pregnadienolone acetate.
abstract: A set of solanidine analogs with antiproliferative properties were recently synthetized from pregnadienolone acetate, which occurs in Nature. The aim of the present study was an in vitro characterization of their antiproliferative action and an investigation of their multidrug resistance-reversal activity on cancer cells. Six of the compounds elicited the accumulation of a hypodiploid population of HeLa cells, indicating their apoptosis-inducing character, and another one caused cell cycle arrest at the G2/M phase. The most effective agents inhibited the activity of topoisomerase I, as evidenced by plasmid supercoil relaxation assays. One of the most potent analogs down-regulated the expression of cell-cycle related genes at the mRNA level, including tumor necrosis factor alpha and S-phase kinase-associated protein 2, and induced growth arrest and DNA damage protein 45 alpha. Some of the investigated compounds inhibited the ABCB1 transporter and caused rhodamine-123 accumulation in murine lymphoma cells transfected by human MDR1 gene, expressing the efflux pump (L5178). One of the most active agents in this aspect potentiated the antiproliferative action of doxorubicin without substantial intrinsic cytostatic capacity. The current results indicate that the modified solanidine skeleton is a suitable substrate for the rational design and synthesis of further innovative drug candidates with anticancer activities.
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, Szeged 6720, Hungary. zupko@pharm.u-szeged.hu.
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, Szeged 6720, Hungary. molnarjudit85@freemail.hu.
authors.forename: Judit
authors.initials: J
authors.lastname: Molnár
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, Szeged 6720, Hungary. rethyborbala@pharm.u-szeged.hu.
authors.forename: Borbála
authors.initials: B
authors.lastname: Réthy
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, Szeged 6720, Hungary. minorics@pharm.u-szeged.hu.
authors.forename: Renáta
authors.initials: R
authors.lastname: Minorics
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged 6720, Hungary. frank@chem.u-szeged.hu.
authors.forename: Eva
authors.initials: E
authors.lastname: Frank
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged 6720, Hungary. wolfling@chem.u-szeged.hu.
authors.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.affiliation: Institute of Microbiology and Immunology, University of Szeged, Dóm tér 10, Szeged 6720, Hungary. molnar.jozsef@med.u-szeged.hu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.affiliation: Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged 6720, Hungary. imre@bioch.szote.u-szeged.hu.
authors.forename: Imre
authors.initials: I
authors.lastname: Ocsovszki
authors.affiliation: Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir 35100, Turkey. zeki.topcu@ege.edu.tr.
authors.forename: Zeki
authors.initials: Z
authors.lastname: Topcu
authors.affiliation: Department of Obstetrics and Gynaecology, University of Szeged, Semmelweis u. 1, Szeged 6725, Hungary. bito.tamas@med.u-szeged.hu.
authors.forename: Tamás
authors.initials: T
authors.lastname: Bitó
authors.affiliation: Laboratory of Functional Genomics, Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged 6726, Hungary. puskas.szbk@gmail.com.
authors.forename: László G
authors.initials: LG
authors.lastname: Puskás
mesh_terms: D000085:Acetates / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004144:Diosgenin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000737:chemistry / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011244:Pregnadienediols / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000085:Acetates; D011244:Pregnadienediols; D004317:Doxorubicin; D004144:Diosgenin; C013255:solanidine