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Hypoxia can impair doxorubicin resistance of non-small cell lung cancer cells by inhibiting MRP1 and P-gp expression and boosting the chemosensitizing effects of MRP1 and P-gp blockers

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Abstract

Background

Non-small cell lung cancers (NSCLCs) frequently exhibit resistance to therapeutic drugs, which seriously hampers their treatment. Here, we set out to assess the roles of the multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-gp) in the doxorubicin (DOX) resistance of NSCLC cells, as well as the putative therapeutic efficacy of MRP1 and P-gp blockers on DOX-treated NSCLC cells.

Methods

The impact of DOX on cell survival, DOX efflux and MRP1 and P-gp expression was assessed in 5 different NSCLC-derived cell lines (parental CH27, A549, H1299, H460, and DOX resistant CH27) in the absence or presence of MK571 (MRP1 inhibitor) or Verapamil (P-gp inhibitor), under both normoxic and hypoxic conditions.

Results

We found that in response to DOX treatment, NSCLC cells that express high levels of MRP1 and P-gp (such as CH27) showed a better DOX efflux and a higher DOX resistance. MK571 and Verapamil were found to abolish DOX resistance and to act as chemosensitizers for DOX therapy in all cell lines tested. We also found that hypoxia could inhibit MRP1 and P-gp expression in a HIF-1α-dependent manner, abolish DOX resistance and boost the chemosensitizer effect of MK571 and Verapamil on DOX treatment of all the NSCLC cells tested, except the DOX-resistant CH27 cells.

Conclusions

From our data we conclude that MRP1 and P-gp play critical roles in the DOX resistance of the NSCLC cells tested. MRP1 and P-gp targeted therapy using MK571, Verapamil, CoCl2 or ambient hypoxia appeared to be promising in abolishing the DOX efflux and DOX resistance of the NSCLC cells. The putative therapeutic efficacies of MRP1 and/or P-gp blockers on NSCLC cells are worthy of note.

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Acknowledgments

This work was supported by grants TCVGH-NCHU1017608, TCVGH-NCHU1027613 and NSC-99-2320-B-005-006-MY3 and the ATU plan under the Ministry of Education, Taiwan, Republic of China. We thank Dr. Li-Chiung Lin for technical support.

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Authors and Affiliations

  1. Department of Life Sciences, National Chung Hsing University, 145, Hsing-Da Rd, Taichung, 40227, Taiwan

    Yu-Lun Chen & Chi-Mei Hsueh

  2. Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

    Tsung-Ying Yang, Kun-Chieh Chen & Chieh-Liang Wu

  3. Center for Quality Management, Taichung Veterans General Hospital, Taichung, Taiwan

    Chieh-Liang Wu

  4. Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan

    Shih-Lan Hsu

  5. Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

    Chi-Mei Hsueh

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  1. Yu-Lun Chen
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Chen, YL., Yang, TY., Chen, KC. et al. Hypoxia can impair doxorubicin resistance of non-small cell lung cancer cells by inhibiting MRP1 and P-gp expression and boosting the chemosensitizing effects of MRP1 and P-gp blockers. Cell Oncol. 39, 411–433 (2016). https://doi.org/10.1007/s13402-016-0285-5

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