ABCB1-overexpressing MDCK-II cells are hypersensitive to 3-bromopyruvic acid

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• 作者：Izabela Sadowska-Bartosz^a ; ^{isadowska@poczta.fm" class="auth_mail" title="E-mail the corresponding author} ; Jacek Grębowski^b ; Ewa Kępka^b ; Maciej Studzian^b ; Grzegorz Bartosz^a ; ^b ; Łukasz Pułaski^b ; ^c
• 关键词：MDKC-II cells ; ABCB1 protein ; ABCG2 protein ; Multidrug resistance ; 3-Bromopyruvate ; ATP
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：162
• 期：Complete
• 页码：138-144
• 全文大小：805 K

文摘

Cancer cells, due to the Warburg effect, are more dependent on glycolysis than normal cells, so glycolytic inhibitor 3-bromopyruvic acid (3-BP) was proposed as a promising candidate for anticancer therapy. Overexpression of multidrug transporters is the main reason of resistance of cancer cells to chemotherapy. As the activity of multidrug transporters imposes an energetic burden on the cells, it can be expected that inhibition of ATP generation may exert a selective cytotoxicity to cells overexpressing multidrug transporters. The aim of this study was to compare the effect of 3-BP on the survival and ATP level in MDCK-II cells and MDCK-II cells overexpressing ABCB1 (Pgp) or ABCG2 (BCRP).

Main methods

Cell survival was measured with resazurin and with neutral red. ATP level was assayed with luciferin/luciferase kit. Luteolin transport was measured by an original method described in the paper.

Key findings

3-BP (10–200 μM) induced a decrease of ATP level after 1-h incubation in all cell lines studied, more drastically in ABCB1-overexpressing cells. 50 and 200 μM 3-BP significantly decreased cell viability; the effect was more pronounced for ABCB1-overexpressing cells. PSC833, inhibitor of ABCB1, ameliorated the toxic effect of 3-BP on MDCK-II ABCB1 cells and MDCK-II cells. 3-BP inhibited luteolin transport in MDCK-II ABCG2 cells.

Significance

These results indicate that 3-BP shows selective toxicity against ABCB1- but not ABCG2-overexpressing cells, apparently due to enhanced ATP depletion but in a manner independent of the transport activity of Pgp, suggesting a novel mechanism of hypersensitivity of ABCB1-overexpressing cells to 3-BP.