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Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1α

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Abstract

Purpose

Hypoxic tumor cells overexpressing hypoxia-inducible factor 1alpha (HIF-1α) are generally resistant to chemo/radiotherapy. We have reported that Se-methylselenocysteine (MSC) therapeutically enhances the efficacy and selectivity of irinotecan against human tumor xenografts. The aim of this study was to delineate the mechanism responsible for the observed efficacy targeting on HIF-1α and its transcriptionally regulated genes VEGF and CAIX.

Methods

We investigated the mechanism of HIF-1α inhibition by MSC and its critical role in the therapeutic outcome by generating HIF-1α stable knockdown (KD) human head and neck squamous cell carcinoma, FaDu by transfecting HIF-1α short hairpin RNA.

Results

While cytotoxic efficacy in combination with methylselenic acid (MSA) with SN-38 (active metabolites of MSC and irinotecan) could not be confirmed in vitro against normoxic tumor cells, the hypoxic tumor cells were more sensitive to the combination. Reduction in HIF-1α either by MSA or shRNA knockdown resulted in significant increase in cytotoxicity of SN38 in vitro against hypoxic, but not the normoxic tumor cells. Similarly, in vivo, either MSC in combination with irinotecan treatment of parental xenografts or HIF-1α KD tumors treated with irinotecan alone resulted in comparable therapeutic response and increase in the long-term survival of mice bearing FaDu xenografts.

Conclusions

Our results show that HIF-1α is a critical target for MSC and its inhibition was associated with enhanced antitumor activity of irinotecan. Inhibition of HIF-1α appeared to be mediated through stabilization of PHD2, 3 and downregulation of ROS by MSC. Thus, our findings support the development of MSC as a HIF-1α inhibitor in combination chemotherapy.

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Acknowledgments

This study was supported by a grant from National Cancer Institute 1R21CA133682-01A2 (S. Chintala) and a Comprehensive Cancer Center Support grant CA 016056 from National Cancer Institute, Bethesda, Maryland, USA. We thank Dr. Harry Slocum for the review of this manuscript, Dr. Jaromir Pastorek for providing antibody M75 for CAIX studies, and Rebecca Dean for technical support.

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Authors and Affiliations

  1. Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Sreenivasulu Chintala, Károly Tόth, Shousong Cao, Farukh A. Durrani & Youcef M. Rustum

  2. Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Mary M. Vaughan

  3. Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84132, USA

    Randy L. Jensen

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  1. Sreenivasulu Chintala
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  2. Károly Tόth
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  7. Youcef M. Rustum
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Correspondence to Sreenivasulu Chintala.

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Chintala, S., Tόth, K., Cao, S. et al. Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1α. Cancer Chemother Pharmacol 66, 899–911 (2010). https://doi.org/10.1007/s00280-009-1238-8

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  • DOI: https://doi.org/10.1007/s00280-009-1238-8

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