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Open Access 16-01-2024 | Melanoma | Original Article

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

Authors: Thamir M. Mahgoub, Emmet J. Jordan, Amira F. Mahdi, Veronika Oettl, Stefanie Huefner, Norma O’Donovan, John Crown, Denis M. Collins

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2024

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Abstract

Purpose

Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemotherapies 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 efflux transporter overexpression (DLKP-A), and drug efflux transporter ATPase assays.

Results

Melanoma cell lines exhibit a low but variable protein and RNA expression of drug efflux 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 profile 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 significantly 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 confirms 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 efflux transporter inhibitors for hard-to-treat MDR melanoma.
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Metadata
Title
Evaluation of ABT-751, a novel anti-mitotic agent able to overcome multi-drug resistance, in melanoma cells
Authors
Thamir M. Mahgoub
Emmet J. Jordan
Amira F. Mahdi
Veronika Oettl
Stefanie Huefner
Norma O’Donovan
John Crown
Denis M. Collins
Publication date
16-01-2024
Publisher
Springer Berlin Heidelberg
Keywords
Melanoma
Melanoma
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2024
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-023-04624-6

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