title: Ecdysteroids sensitize MDR and non-MDR cancer cell lines to doxorubicin, paclitaxel, and vincristine but tend to protect them from cisplatin.
abstract: Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR) mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-hydroxyecdysone (1) and its mono- (2) and diacetonide (3) derivatives to sensitize various MDR and non-MDR cancer cell lines towards doxorubicin, paclitaxel, vincristine, or cisplatin. Drug IC50 values with or without ecdysteroid were determined by MTT assay. Compound 3 significantly sensitized all cell lines to each chemotherapeutic except for cisplatin, whose activity was decreased. In order to overcome solubility and stability issues for the future in vivo administration of compound 3, liposomal formulations were developed. By means of their combination index values obtained via checkerboard microplate method, a formulation showed superior activity to that of compound 3 alone. Because ecdysteroids act also on non-ABCB1 expressing (sensitive) cell lines, our results demonstrate that they do not or not exclusively exert their adjuvant anticancer activity as ABCB1 inhibitors, but other mechanisms must be involved, and they opened the way towards their in vivo bioactivity testing against various cancer xenografts.
authors.affiliation: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, Szeged 6720, Hungary ; Unidade de Parasitologia e Microbiologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal.
authors.forename: Ana
authors.identifier: 0000-0002-8541-7440
authors.initials: A
authors.lastname: Martins
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Szeged, Eötvös Ucta 6, Szeged 6720, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Sipos
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Szeged, Eötvös Ucta 6, Szeged 6720, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Dér
authors.affiliation: Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Eötvös Ucta 6, Szeged 6720, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Csábi
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Miklos
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna, Austria ; Institute of Inorganic Chemistry and Research Platform "Translational Cancer Therapy Research", University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: First Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest 1085, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Zalatnai
authors.affiliation: Centro de Malária e Outras Doenças Tropicais (CMDT), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal.
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
authors.affiliation: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, Szeged 6720, Hungary.
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Szeged, Eötvös Ucta 6, Szeged 6720, Hungary.
authors.forename: Piroska
authors.initials: P
authors.lastname: Szabó-Révész
authors.affiliation: Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Eötvös Ucta 6, Szeged 6720, Hungary.
authors.forename: Attila
authors.identifier: 0000-0003-0074-3472
authors.initials: A
authors.lastname: Hunyadi
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D026461:Ecdysteroids / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D026461:Ecdysteroids; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin