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Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1α in tumor and normal cells

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Abstract

Purpose

The anthracycline antibiotic doxorubicin (DOX) has been used successfully for treating various types of cancers. However, the therapeutic efficacy of DOX was greatly restricted by its cumulative dose-related cardiotoxicity and common side effects such as bone marrow and immune suppression. Quercetin had better cardioprotective and hepatoprotective activities. The present study was to observe whether quercetin could improve therapeutic index of DOX and explore its mechanisms.

Methods

Effects of quercetin on doxorubicin (DOX)-induced cytotoxicity were investigated in 4T1 cells and murine spleen cells by methylthiazoletetrazolium assay, flow cytometry and single cell gel electrophoresis. Influences of quercetin on therapeutic efficacy and systemic toxicity of DOX were evaluated in BALB/c mice with 4T1 breast cancer. Hypoxia-inducible factor-1 alpha (HIF-1α) in tumor and normal cells was examined to explore mechanisms of quercetin by Western blot and enzyme-linked immunosorbent assay.

Results

In vitro, quercetin at dose less than 100 μM had only slight effects on cell viability and DOX-induced cytotoxicity in 4T1 cells under normoxia, but it could reverse 4T1 cell resistance to DOX under hypoxia and protect spleen cells against DOX-induced cytotoxicity. In vivo, quercetin suppressed tumor growth and prolonged survival in BALB/c mice bearing 4T1 breast cancer. Importantly, quercetin enhanced therapeutic efficacy of DOX and simultaneously reduced DOX-induced toxic side effects. Further study showed that quercetin suppressed intratumoral HIF-1α in a hypoxia-dependent way but increased its accumulation in normal cells. HIF-1α siRNA abolished effects of quercetin on both tumor and normal cells.

Conclusions

These results suggested that quercetin could improve therapeutic index of DOX by its opposing effects on HIF-1α in tumor and normal cells, and was a promising candidate as anticancer agents.

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Acknowledgments

This work was supported by grants from the State Key Development Plan Project (2006CB705706) and National Natural Science Foundation of China (90606019). We thank Xu Zhang and Wenfang Meng for excellent animal care. We also thank professor Wei Liang for help with submission of the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Pharmaceutical College of Henan University, Jinming District, 475001, Kaifeng, Henan, China

    Gangjun Du, Haihong Lin, Mei Wang, Shuo Zhang, Xianchuang Wu, Linlin Lu, Liyan Ji & Lijuan Yu

  2. Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, 100101, Beijing, China

    Gangjun Du & Shuo Zhang

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  1. Gangjun Du
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  2. Haihong Lin
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Correspondence to Gangjun Du.

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G. Du and H. Lin have contributed equally to this work.

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Du, G., Lin, H., Wang, M. et al. Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1α in tumor and normal cells. Cancer Chemother Pharmacol 65, 277–287 (2010). https://doi.org/10.1007/s00280-009-1032-7

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  • DOI: https://doi.org/10.1007/s00280-009-1032-7

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