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

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Evaluation of ABT-751, a novel anti-mitotic agent able to overcome multi-drug resistance, in melanoma cells
Cancer Chemotherapy and Pharmacology ( IF 2.7 ) Pub Date : 2024-01-16 , DOI: 10.1007/s00280-023-04624-6
Thamir M Mahgoub ₁ , Emmet J Jordan ₁ , Amira F Mahdi _{1,

2} , Veronika Oettl ₁ , Stefanie Huefner ₁ , Norma O'Donovan ₁ , John Crown _{1,

3} , Denis M Collins ₁

Affiliation

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.

中文翻译：

ABT-751（一种能够克服多重耐药性的新型抗有丝分裂剂）在黑色素瘤细胞中的评价

目的

药物外排转运蛋白相关的多药耐药性（MDR）是使用紫杉烷化疗治疗转移性黑色素瘤的潜在限制。 ABT-751 是一种口服生物可利用的微管结合剂，能够克服 MDR，并被提议作为紫杉烷类疗法的替代品。

方法

本研究利用七种黑色素瘤细胞系模型、公开的基因表达和药物敏感性数据库、MDR 药物外排转运蛋白过度表达 (DLKP-A) 的肺癌细胞系模型和药物外排转运蛋白 ATP 酶，在体外比较 ABT-751 和紫杉烷类药物化验。

结果

黑色素瘤细胞系的药物外排转运蛋白 P-gp、BCRP 和 MDR3 的蛋白质和 RNA 表达水平较低，但变化较大。 P-gp 和 MDR3 的表达与紫杉烷类药物的敏感性相关，但与 ABT-751 的敏感性无关。在黑色素瘤细胞系组中，ABT-751 的抗增殖 IC ₅₀高于紫杉烷类多西紫杉醇和紫杉醇，但处于临床可实现的参数范围内。 ABT-751 IC ₅₀不受 DKLP-A 细胞中 P-gp 过表达的影响，与 DLKP 亲本对照相比，DKLP-A 细胞对 P-gp 底物紫杉烷表现出强抗性。在紫杉醇治疗中添加 ABT-751 显着降低了细胞增殖，表明 MDR 有所逆转。 ATPase 活性测定表明 ABT-751 是一种潜在的 BCRP 底物，能够抑制 P-gp ATPase 活性。