Abstract
The triple negative basal-like (TNBL) breast carcinoma is an aggressive and unfavorable prognosis disease. Inhibitors of poly(ADP-ribose) polymerase such as Olaparib could represent a promising targeted therapy but their sensitivity against Multidrug Resistance proteins (MDR), which causes resistance, is not well defined. Thus, our work focused on the analysis of P-gp and BCRP coexpression in the SUM1315 TNBL human cell line, in correlation with Olaparib intracellular concentration. Western blot analyses showed a clear coexpression of P-gp and BCRP in SUM1315 cells. A low cytotoxic Olaparib treatment clearly led to an increased expression of both BCRP and P-gp in these cells. Indeed, after 1.5 h of treatment, BCRP expression was increased with a 1.8 fold increase rate. Then, P-gp took over from 3 h to 15 h with an average increase rate of 1.8 fold, and finally returned to control value at 24 h. HPLC-UV analyses showed that, in the same treatment conditions, the intracellular Olaparib concentration increased from 1 h to 3 h and remained relatively stable until 24 h. Results suggest that the resistance mechanism induced by Olaparib in TNBL SUM1315 cell line may be overpassed if a cytotoxic and stable intracellular level of the drug can be maintained.
Highlights
In young women, shows an unusual sarcoma-like pattern of metastasis, and is highly associated with constitutive mutations of the BRCA1 gene[2]
Multidrug Resistance transporters (MDR) transporters belong to the “ATP-binding cassette” (ABC) superfamily of proteins, which were highly conserved during evolution
The two major MDR proteins, Permeability-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), which belong to the ABCB and ABCG subfamily, respectively, have been showed to be frequently expressed in human cancer
Summary
In young women, shows an unusual sarcoma-like pattern of metastasis, and is highly associated with constitutive mutations of the BRCA1 gene[2]. The management of TNBL carcinomas is not standardized yet It is based on the use of classical cytotoxic drugs i.e. anthracyclines and/or taxanes, conventional chemotherapy is not always effective in these tumors. MDR proteins act as xenobiotics efflux pumps able to transport various drugs out of cells They recognize a large variety of substrates with different structures and properties, including many classical chemotherapeutic agents[19]. MDR transporters are considered to be the essential part of an innate cellular defense system, the “chemoimmunity” network, which has a number of reminiscent features of classical immunology[19] In this context, the present work focused on the analysis of P-gp and BCRP coexpression in the SUM1315 TNBL human cell line, in correlation with Olaparib intracellular concentration
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