Effective cancer chemotherapy treatment requires both therapy delivery and retention by malignant cells. Cancer cell overexpression of the multidrug transmembrane transporter gene ABCB1 (MDR1, multi-drug resistance protein 1) thwarts therapy retention, leading to a drug-resistant phenotype. We explored the phenotypic impact of ABCB1 overexpression in normal human mammary epithelial cells (HMECs) via acute adenoviral delivery and in breast cancer cell lines with stable integration of inducible ABCB1 expression. One hundred sixty-two genes were differentially expressed between ABCB1-expressing and GFP-expressing HMECs, including the gene encoding the cyclooxygenase-2 protein, PTGS2. Several breast cancer cell lines with inducible ABCB1 expression demonstrated sensitivity to the 5-lipoxygenase, cyclooxygenase-1/2 inhibitor tepoxalin in two-dimensional drug response assays, and combination treatment of tepoxalin either with chemotherapies or with histone deacetylase (HDAC) inhibitors improved therapeutic efficacy in these lines. Moreover, selection for the ABCB1-expressing cell population was reduced in three-dimensional co-cultures of ABCB1-expressing and GFP-expressing cells when chemotherapy was given in combination with tepoxalin. Further study is warranted to ascertain the clinical potential of tepoxalin, an FDA-approved therapeutic for use in domesticated mammals, to restore chemosensitivity and improve drug response in patients with ABCB1-overexpressing drug-resistant breast cancers.

有效的癌症化学疗法需要恶性细胞的治疗递送和保留。多药跨膜转运蛋白基因ABCB1（MDR1，多药耐药蛋白 1）的癌细胞过度表达阻碍了治疗保留，导致耐药表型。我们通过急性腺病毒递送探索了ABCB1在正常人乳腺上皮细胞 (HMEC) 中过表达的表型影响，以及在稳定整合可诱导ABCB1表达的乳腺癌细胞系中的表型影响。162 个基因在表达ABCB1和表达GFP的 HMEC之间差异表达，包括编码环氧合酶 2 蛋白PTGS2 的基因. 具有诱导型ABCB1表达的几种乳腺癌细胞系在二维药物反应测定中表现出对 5-脂氧合酶、环氧合酶-1/2 抑制剂替泊沙林的敏感性，以及替泊沙林与化疗或组蛋白脱乙酰酶 (HDAC) 抑制剂的联合治疗改善了治疗在这些方面的功效。此外，在表达ABCB1和GFP的三维共培养物中减少了对表达ABCB1的细胞群的选择- 当化疗与替泊沙林联合使用时表达细胞。需要进一步研究来确定替泊沙林（一种 FDA 批准的用于驯养哺乳动物的治疗剂）在ABCB1过度表达的耐药性乳腺癌患者中恢复化学敏感性和改善药物反应的临床潜力。