Acidity is one of the main mechanism for hypoxia triggering chemoresistance to mitoxanthrone (MX) in the huma breast

cancer MCF-7 cell line

Background: The development of multidrug resistance (MDR) and subsequent relapse while receiving therapy is one of the major obstacles to effective cancer treatment. Hypoxia is associated with the development of resistance to chemotherapeutic agents in tumors. The aim of this study is to investigate the effects and mechanisms of hypoxia on the chemoresistance in breast cancer cells. Materials and Methods: Cell viability assay, flow cytometry assay, reverse transcription-PCR, and Western blotting for the kinetic changes of mRNA and protein of hypoxia-inducible factors-1α (HIF-1α) and ATP-binding cassette sub-family G member 2 (ABCG2) were used to study the effects of hypoxia on the chemosensitivity of mitoxanthrone (MX) of MCF-7 and MCF-7/MX breast cancer cell lines sub-jected to hypoxia. Results: Hypoxia (1% O2) 18 hours decreased the MX sensitivity of MCF-7 cells. Although the levels of mRNA and protein of HIF-1α and ABCG2 in MCF-7 and MCF-7/MX cells were affected under 1% oxygen tension, however, a specific inhibitor of ABCG2, Ko143 did not affect the MX sensitivity of MCF-7 cells subjected to hypoxia for 18 hours. The acidified media (pH 6.5) by hypoxia significantly decreased the retention of MX in MCF-7 cells. Conclusion: Acidity resulting from the hypoxia may cause chemore-sistance to MX through a decrease of intracellular MX. As such, targeting the highly acidic microenvironments of tumors may hold therapeutic promise as a means of overcoming the chemoresistance of cancer.

Hypoxia; Hypoxia-inducible factors-1α (HIF-1α); Chemoresistance; ATP-binding cassette sub-family G member 2 (ABCG2); Acidity.

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