Targeting ABCB1 and ABCC1 with their Specific Inhibitor CBT-1® can Overcome Drug Resistance in Osteosarcoma

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• High-grade osteosarcoma (OS) treatment response is limited by drug resistance.
• ABCB1 (MDR1/P-glycoprotein) overexpression is a known mechanism, but other ATP binding cassette (ABC) transporters also contribute to multidrug resistance.
• Identifying key transporters is crucial for developing strategies against unresponsive OS.

Purpose of the Study:

• To investigate the impact of various ATP binding cassette (ABC) transporters on drug resistance in human osteosarcoma (OS) cell lines.
• To evaluate the efficacy of CBT-1 (Tetrandrine), an inhibitor of ABCB1 and ABCC1, in overcoming chemotherapy resistance in OS.
• To explore potential new therapeutic options for relapsed or unresponsive OS patients.

Main Methods:

• Utilized a panel of 6 drug-sensitive and 20 drug-resistant human OS cell lines.
• Assessed the expression and contribution of ABC transporters to drug resistance.
• Evaluated the in vitro activity of CBT-1 in combination with conventional chemotherapeutic agents.

Main Results:

• ABCC1 was identified as a significant transporter associated with the degree of drug resistance in OS cells, in addition to ABCB1.
• The orally administrable inhibitor CBT-1 effectively reverted ABCB1/ABCC1-mediated resistance against doxorubicin.
• CBT-1 also demonstrated efficacy in overcoming resistance to second-line OS treatment drugs like taxotere, etoposide, and vinorelbine.

Conclusions:

• Inhibiting both ABCB1 and ABCC1 transporters with CBT-1 shows promise in overcoming chemotherapy resistance in osteosarcoma.
• CBT-1, in combination with conventional chemotherapy, may offer a novel therapeutic strategy for patients with relapsed or refractory OS.
• This approach could improve treatment outcomes for patients with limited therapeutic options.