PDGFRβ and HIF-1α inhibition with imatinib and radioimmunotherapy of experimental prostate cancer

Yu Kimura, Kotaro Inoue, Michio Abe, Jessica Nearman, Janina Baranowska-Kortylewicz

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The clinical application of radioimmunotherapy (RIT) as a single modality in the treatment of prostate cancer is held back because of poor tumor responses to RIT and unacceptable normal tissue toxicities. The purpose of reported here studies was to develop a multimodality approach to RIT of prostate cancer that includes imatinib, a potent PDGFRβ inhibitor, and in the course of these studies to define the mechanism of imatinib effects on RIT. Hypothesized interactions between these two modalities depend on the reduction of tumor interstitial fluid pressure with the subsequent increase of 131ICC49 uptake into the tumor, and the inhibition of HIF-1α resulting in the improved tumor radiosensitivity. Levels of HIF-1α, IGF-1, PDGF-BB, phospho-PDGFRβ and VEGF in response to imatinib were examined in PC-3 human prostate adenocarcinoma cells in vitro and in xenografts. RIT was based on 131ICC49 and it was augmented with imatinib. Although PDGFRβ appears to be functional in PC-3 tumors, the effect of imatinib on the tumor interstitial fluid pressure was insignificant. PC-3 cells and PC-3 xenografts express constitutive HIF-1α, which was significantly inhibited by imatinib. Reduced levels of HIF-1α were accompanied by the notable suppression of IGF-1. Simultaneously the increase in tumor levels of mouse and human PDGF-BB was observed. Improved PC-3 responses to RIT+imatinib treatment were significant and lasted approximately two weeks. Tumor doubling times in mice treated with 131ICC49+imatinib were 21.6 ± 0.7 days compared to 17.2 ± 0.5 days in 131ICC49+PBS-treated control mice. Imatinib alone had no effect on the tumor growth. In conclusion, imatinib inhibits HIF-1α expression in PC-3 tumors and improves RIT, but it has no effect on VEGF indicating absence of anti-angiogenic effects. There is a significant time- and dose-dependent reduction in the expression of IGF-1 suggesting an alternative pathway of imatinib-regulated HIF-1α expression leading to the improved PC-3 responses to RIT.

Original languageEnglish (US)
Pages (from-to)1763-1772
Number of pages10
JournalCancer Biology and Therapy
Volume6
Issue number11
DOIs
StatePublished - Nov 2007

Keywords

  • Hypoxia inducible factor-1α
  • Imatinib
  • Insulin-like growth factor-1
  • PC-3 xenografts
  • Platelet derived growth factor
  • Prostate cancer
  • Radioimmunotherapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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