title: Targeting ABCB1 and ABCC1 with their Specific Inhibitor CBT-1® can Overcome Drug Resistance in Osteosarcoma.
abstract: Clinical treatment response achievable with conventional chemotherapy in high-grade osteosarcoma (OS) is severely limited by the presence of intrinsic or acquired drug resistance, which in previous studies has been mainly addressed for overexpression of ABCB1 (MDR1/P-glycoprotein). This study was aimed to estimate the impact on OS drug resistance of a group of ATP binding cassette (ABC) transporters, which in other human tumors have been associated with unresponsiveness to the drugs that represent the backbone of multidrug treatment regimens for OS (doxorubicin, methotrexate, cisplatin). By using a group of 6 drug-sensitive and 20 drug-resistant human OS cell lines, the most relevant transporter which proved to be associated with the degree of drug resistance in OS cells, in addition to ABCB1, was ABCC1. We therefore evaluated the in vitro activity of the orally administrable ABCB1/ABCC1 inhibitor CBT-1(®) (Tetrandrine, NSC-77037). We found that in our OS cell lines this agent was able to revert the ABCB1/ABCC1-mediated resistance against doxorubicin, as well as against the drugs used in second-line OS treatments that are substrates of these transporters (taxotere, etoposide, vinorelbine). Our findings indicated that inhibiting ABCB1 and ABCC1 with CBT-1(®), used in association with conventional chemotherapeutic drugs, may become an interesting new therapeutic option for unresponsive or relapsed OS patients.
authors.forename: Marilù
authors.initials: M
authors.lastname: Fanelli
authors.forename: Claudia Maria
authors.initials: CM
authors.lastname: Hattinger
authors.forename: Serena
authors.initials: S
authors.lastname: Vella
authors.forename: Elisa
authors.initials: E
authors.lastname: Tavanti
authors.forename: Francesca
authors.initials: F
authors.lastname: Michelacci
authors.forename: Beth
authors.initials: B
authors.lastname: Gudeman
authors.forename: Daryl
authors.initials: D
authors.lastname: Barnett
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: Pharmacogenomics and Pharmacogenetics Research Unit, Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Via di Barbiano 1/10, I-40136 Bologna, Italy. massimo.serra@ior.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D044182:Benzylisoquinolines / Q000494:pharmacology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008856:Microscopy, Fluorescence; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C009438:tetrandrine; C421109:multidrug resistance-associated protein 1