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Nilotinib potentiates anticancer drug sensitivity in murine ABCB1-, ABCG2-, and ABCC10-multidrug resistance xenograft
Amit K Tiwari1, Kamlesh Sodani, Chun-Ling Dai
1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Abstract:
A panel of clinically used tyrosine kinase inhibitors were compared and nilotinib was found to most potently sensitize specific anticancer agents by blocking the functions of ABCB1/P-glycoprotein, ABCG2/BCRP and ABCC10/MRP7 transporters involved in multi-drug resistance. Nilotinib appreciably enhanced the antitumor response of (1) paclitaxel in the ABCB1- and novel ABCC10-xenograft models, and (2) doxorubicin in a novel ABCG2-xenograft model. With no apparent toxicity observed in the above models, nilotinib attenuated tumor growth synergistically and increased paclitaxel concentrations in ABCB1-overexpressing tumors. The beneficial actions of nilotinib warrant consideration as viable combinations in the clinic with agents that suffer from MDR-mediated insensitivity.
Insights
Nilotinib effectively overcomes multi-drug resistance by inhibiting key transporters. This tyrosine kinase inhibitor enhances anticancer drug efficacy, showing promise for clinical combination therapies against resistant tumors.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Multi-drug resistance (MDR) significantly limits the effectiveness of chemotherapy.
- ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1), BCRP (ABCG2), and MRP7 (ABCC10), are major mediators of MDR.
- Targeting these transporters is a key strategy to restore chemosensitivity.
Purpose of the Study:
- To evaluate clinically used tyrosine kinase inhibitors (TKIs) as sensitizers for anticancer agents.
- To identify TKIs that can overcome resistance mediated by ABCB1, ABCG2, and ABCC10 transporters.
- To assess the efficacy and toxicity of nilotinib in combination with chemotherapy in preclinical models.
Main Methods:
- Screening of clinically used TKIs for their ability to inhibit ABCB1, ABCG2, and ABCC10.
- Testing nilotinib in combination with paclitaxel and doxorubicin in relevant xenograft models.
- Evaluating tumor growth, drug concentrations, and toxicity in treated animal models.
Main Results:
- Nilotinib demonstrated potent inhibition of ABCB1, ABCG2, and ABCC10 transporters.
- Nilotinib significantly enhanced the antitumor activity of paclitaxel in ABCB1- and ABCC10-overexpressing models.
- Nilotinib improved the efficacy of doxorubicin in an ABCG2-overexpressing model without apparent toxicity.
- Nilotinib increased paclitaxel concentrations within ABCB1-overexpressing tumors.
Conclusions:
- Nilotinib is a potent sensitizer that overcomes multi-drug resistance mediated by ABCB1, ABCG2, and ABCC10.
- Combination therapy with nilotinib and conventional anticancer agents warrants clinical investigation.
- Nilotinib offers a promising strategy to improve treatment outcomes for patients with MDR cancers.
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