Targeting ABCB1 and ABCC1 with their Specific Inhibitor CBT-1® can Overcome Drug Resistance in Osteosarcoma
Claudia Maria Hattinger,
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,
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.
Keywords: ABC transporters, chemosensitization, chemotherapy, drug resistance, osteosarcoma, tailored treatments.
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