Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, University of Sydney, New South Wales, 2006, Australia.
College of Pharmacy, The University of Mashreq, Baghdad, Iraq.
Pharmacol Rep. 2022 Oct;74(5):998-1010. doi: 10.1007/s43440-022-00396-7. Epub 2022 Jul 30.
The lack of drug targets is an obstacle to the treatment of patients with triple-negative breast cancer (TNBC). At present, non-specific cytotoxic drugs are first-line agents, but the development of resistance is a major problem with these agents. The epidermal growth factor receptor (EGFR) is a potential target in some TNBCs, because its tyrosine kinase activity drives tumorigenesis. Thus, small molecule inhibitors of the EGFR in combination with cytotoxic agents could be important for the treatment of TNBCs.
The present study evaluated the efficacies of clinically approved EGFR inhibitors in combination with the cytotoxic agent ixabepilone in parental and docetaxel-resistant MDA-MB-231 cells (231C and TXT cells, respectively). Cell viability was assessed using MTT reduction assays, cell death pathways were evaluated using annexin V/7-aminoactinomycin D staining and flow cytometry and Western immunoblotting was used to assess the expression of pro- and anti-apoptotic proteins in cells.
Ixabepilone and the EGFR inhibitors gefitinib and vandetanib inhibited 231C and TXT cell proliferation, but the alternate EGFR inhibitors erlotinib and lapatinib were poorly active. Using combination analysis, ixabepilone/vandetanib was synergistic in both cell types, whereas the ixabepilone/gefitinib combination exhibited antagonism. By flow cytometry, ixabepilone/vandetanib enhanced 231C and TXT cell death over that produced by the single agents and also enhanced caspase-3 cleavage and the pro/anti-apoptotic Bcl-2 protein ratios over ixabepilone alone.
These findings suggest that the ixabepilone/vandetanib combination may have promise for the treatment of patients with drug-resistant TNBC.
缺乏药物靶点是治疗三阴性乳腺癌（TNBC）患者的障碍。目前，非特异性细胞毒性药物是一线药物，但这些药物的耐药性发展是一个主要问题。表皮生长因子受体（EGFR）是一些 TNBC 的潜在靶点，因为其酪氨酸激酶活性驱动肿瘤发生。因此，EGFR 的小分子抑制剂与细胞毒性药物联合使用可能对治疗 TNBC 很重要。
本研究评估了临床上批准的 EGFR 抑制剂与细胞毒性药物伊沙匹隆联合用于亲本和多西紫杉醇耐药 MDA-MB-231 细胞（分别为 231C 和 TXT 细胞）的疗效。使用 MTT 还原测定评估细胞活力，使用 Annexin V/7-氨基放线菌素 D 染色和流式细胞术评估细胞死亡途径，并使用 Western 免疫印迹评估细胞中促凋亡和抗凋亡蛋白的表达。
伊沙匹隆和 EGFR 抑制剂吉非替尼和凡德他尼抑制 231C 和 TXT 细胞增殖，但其他 EGFR 抑制剂厄洛替尼和拉帕替尼活性较差。使用组合分析，伊沙匹隆/凡德他尼在两种细胞类型中均表现出协同作用，而伊沙匹隆/吉非替尼组合则表现出拮抗作用。通过流式细胞术，伊沙匹隆/凡德他尼增强了 231C 和 TXT 细胞死亡，超过了单一药物的作用，并且还增强了 caspase-3 切割和促凋亡/抗凋亡 Bcl-2 蛋白比值，超过了伊沙匹隆单独作用。
这些发现表明，伊沙匹隆/凡德他尼联合用药可能有希望用于治疗耐药性 TNBC 患者。
