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Evaluation of ABT‑751, a novel anti‑mitotic agent able to overcome multi‑drug resistance, in melanoma cells

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journal contribution
posted on 2024-02-14, 10:30 authored by Thamir Mahgoub, Emmet J. Jordan, Amira MahdiAmira Mahdi, Veronika Oettl, Stefanie Huefner, Norma O’Donovan, John Crown, Denis M Collins

Purpose Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemo-therapies for the treatment of metastatic melanoma. ABT-751 is an orally bioavailable microtubule-binding agent capable of overcoming MDR and proposed as an alternative to taxane-based therapies. Methods This study compares ABT-751 to taxanes in vitro, utilizing seven melanoma cell line models, publicly available gene expression and drug sensitivity databases, a lung cancer cell line model of MDR drug efux transporter overexpression (DLKP-A), and drug efux transporter ATPase assays. Results Melanoma cell lines exhibit a low but variable protein and RNA expression of drug efux transporters P-gp, BCRP, and MDR3. Expression of P-gp and MDR3 correlates with sensitivity to taxanes, but not to ABT-751. The anti-proliferative IC50 profle of ABT-751 was higher than the taxanes docetaxel and paclitaxel in the melanoma cell line panel, but fell within clinically achievable parameters. ABT-751 IC50 was not impacted by P-gp-overexpression in DKLP-A cells, which display strong resistance to the P-gp substrate taxanes compared to DLKP parental controls. The addition of ABT-751 to paclitaxel treatment signifcantly decreased cell proliferation, suggesting some reversal of MDR. ATPase activity assays suggest that ABT-751 is a potential BCRP substrate, with the ability to inhibit P-gp ATPase activity. Conclusion Our study confrms that ABT-751 is active against melanoma cell lines and models of MDR at physiologically relevant concentrations, it inhibits P-gp ATPase activity, and it may be a BCRP and/or MDR3 substrate. ABT-751 warrants further investigation alone or in tandem with other drug efux transporter inhibitors for hard-to-treat MDR melanoma.



Cancer Chemotherapy and Pharmacology



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