Targeting ABCB1 and ABCC1 with their specific inhibitor CBT-1® can overcome drug resistance in osteosarcoma

Marilù Fanelli, Claudia Maria Hattinger, Serena Vella, Elisa Tavanti, Francesca Michelacci, Beth Gudeman, Daryl Barnett, Piero Picci, Massimo Serra

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)261-274
Number of pages14
JournalCurrent Cancer Drug Targets
Volume16
Issue number3
Publication statusPublished - Mar 1 2016

Keywords

  • ABC transporters
  • Chemosensitization
  • Chemotherapy
  • Drug resistance
  • Osteosarcoma
  • Tailored treatments

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Cancer Research

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