Tepoxalin increases chemotherapy efficacy in drug-resistant breast cancer cells overexpressing the multidrug transporter gene ABCB1

Translational Oncology

Jinfeng Chen¹  Andrea H. Bild²  Jeffrey T. Chang³  Jasmine A. McQuerry⁴ 

[1] Department of Medical Oncology and Therapeutics Research, City of Hope, 1218 S Fifth Avenue, Monrovia, CA 91016, USA;Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;Department of Medical Oncology and Therapeutics Research, City of Hope, 1218 S Fifth Avenue, Monrovia, CA 91016, USA;Department of Oncological Sciences, School of Medicine, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA;

关键词: ABCB1;    Breast cancer;    Drug resistance;    Cyclooxygenase;    Histone deacetylase inhibitor;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown