Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 5, pp 899–911 | Cite as

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

  • Sreenivasulu Chintala
  • Károly Tόth
  • Shousong Cao
  • Farukh A. Durrani
  • Mary M. Vaughan
  • Randy L. Jensen
  • Youcef M. Rustum
Original Article

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.

Keywords

HIF-1α Se-methylselenocysteine Irinotecan Hypoxic tumor cells PHD 

Notes

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.

Conflict of interest statement

None.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Sreenivasulu Chintala
    • 1
  • Károly Tόth
    • 1
  • Shousong Cao
    • 1
  • Farukh A. Durrani
    • 1
  • Mary M. Vaughan
    • 2
  • Randy L. Jensen
    • 3
  • Youcef M. Rustum
    • 1
  1. 1.Department of Cancer BiologyRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of PathologyRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Department of Neurosurgery, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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