Combination strategy targeting the hypoxia inducible factor-1 α with mammalian target of rapamycin and histone deacetylase inhibitors

Henk M W Verheul, Brenda Salumbides, Karen Van Erp, Hans Hammers, David Z. Qian, Tolib Sanni, Peter Atadja, Roberto Pili

Research output: Contribution to journalArticle

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Abstract

Purpose: The hypoxia-inducible factor-1α (HIF-α) is a key regulator of tumor angiogenesis. Mammalian target of rapamycin (mTOR) and histone deacetylase (HDAC) inhibitors suppress tumor-induced angiogenesis by reducing tumor HIF-1 α protein expression. Thus, we hypothesized that combination treatment of rapamycin and the HDAC inhibitor LBH589 has greater antiangiogenic and antitumor activity compared with single agents. Experimental Design: To evaluate the effect of LBH589 and rapamycin on HIF-1 α in human prostate PC3, renal C2 carcinoma cell lines, and endothelial cells (human umbilical vein endothelial cells), we did Western blot analysis. To determine the antitumor activity of LBH589 and rapamycin, cell proliferation assays and xenograft experiments were conducted. Results: Western blotting showed that combination treatment of human umbilical vein endothelial cells, C2 and PC3, significantly reduced HIF-1 α protein expression compared with single agents. Treatment with rapamycin resulted in inhibition of the downstream signals of the mTOR pathway and increased phosphorylation of Akt in C2 cells, whereas the constitutively activated Akt in PC3 cells was not modulated. LBH589 decreased both constitutively expressed and rapamycin-induced phosphorylated Akt levels in PC3 and C2 cell lines. In clonogenic assays, the combination treatment had a greater inhibitory effect in PC3 cells (93 ± 1.4%) compared with single agents (66 ± 9% rapamycin and 43 ± 4% LBH589). Combination of rapamycin and LBH589 significantly inhibited PC3 and C2 in vivo tumor growth and angiogenesis as measured by tumor weight and microvessel density. Conclusions: Combination treatment of mTOR and HDAC inhibitors represents a rational therapeutic strategy targeting HIF-1 α that warrants clinical testing.

Original languageEnglish (US)
Pages (from-to)3589-3597
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number11
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

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Hypoxia-Inducible Factor 1
Histone Deacetylase Inhibitors
Sirolimus
Human Umbilical Vein Endothelial Cells
Western Blotting
Cell Line
Neoplasms
Microvessels
Tumor Burden
Heterografts
panobinostat
Prostate
Proteins
Research Design
Endothelial Cells
Phosphorylation
Cell Proliferation
Carcinoma
Kidney

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Combination strategy targeting the hypoxia inducible factor-1 α with mammalian target of rapamycin and histone deacetylase inhibitors. / Verheul, Henk M W; Salumbides, Brenda; Van Erp, Karen; Hammers, Hans; Qian, David Z.; Sanni, Tolib; Atadja, Peter; Pili, Roberto.

In: Clinical Cancer Research, Vol. 14, No. 11, 01.06.2008, p. 3589-3597.

Research output: Contribution to journalArticle

Verheul, Henk M W ; Salumbides, Brenda ; Van Erp, Karen ; Hammers, Hans ; Qian, David Z. ; Sanni, Tolib ; Atadja, Peter ; Pili, Roberto. / Combination strategy targeting the hypoxia inducible factor-1 α with mammalian target of rapamycin and histone deacetylase inhibitors. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 11. pp. 3589-3597.
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AU - Verheul, Henk M W

AU - Salumbides, Brenda

AU - Van Erp, Karen

AU - Hammers, Hans

AU - Qian, David Z.

AU - Sanni, Tolib

AU - Atadja, Peter

AU - Pili, Roberto

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N2 - Purpose: The hypoxia-inducible factor-1α (HIF-α) is a key regulator of tumor angiogenesis. Mammalian target of rapamycin (mTOR) and histone deacetylase (HDAC) inhibitors suppress tumor-induced angiogenesis by reducing tumor HIF-1 α protein expression. Thus, we hypothesized that combination treatment of rapamycin and the HDAC inhibitor LBH589 has greater antiangiogenic and antitumor activity compared with single agents. Experimental Design: To evaluate the effect of LBH589 and rapamycin on HIF-1 α in human prostate PC3, renal C2 carcinoma cell lines, and endothelial cells (human umbilical vein endothelial cells), we did Western blot analysis. To determine the antitumor activity of LBH589 and rapamycin, cell proliferation assays and xenograft experiments were conducted. Results: Western blotting showed that combination treatment of human umbilical vein endothelial cells, C2 and PC3, significantly reduced HIF-1 α protein expression compared with single agents. Treatment with rapamycin resulted in inhibition of the downstream signals of the mTOR pathway and increased phosphorylation of Akt in C2 cells, whereas the constitutively activated Akt in PC3 cells was not modulated. LBH589 decreased both constitutively expressed and rapamycin-induced phosphorylated Akt levels in PC3 and C2 cell lines. In clonogenic assays, the combination treatment had a greater inhibitory effect in PC3 cells (93 ± 1.4%) compared with single agents (66 ± 9% rapamycin and 43 ± 4% LBH589). Combination of rapamycin and LBH589 significantly inhibited PC3 and C2 in vivo tumor growth and angiogenesis as measured by tumor weight and microvessel density. Conclusions: Combination treatment of mTOR and HDAC inhibitors represents a rational therapeutic strategy targeting HIF-1 α that warrants clinical testing.

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