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Background The molecular chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor la (HIF-1a) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90. Method Human xenograft tumors were generated in mice from H1299 (n = 6 per group) and A549 (n = 4 per group) non-small-cell lung cancer cells, UMSCC38 (n = 5 per group) head and neck cancer cells, MKN45 (n = 5 per group) stomach cancer cells, and PC-3 (n = 3 per group) prostate cancer cells. Tumor-bearing mice were treated with deguelin at 4 or 8 mg/kg or with vehicle (as a control) twice a day by oral gavage for 15-28 days. Protein expression was assessed by western blot analysis. Akt and Hsp90 were assessed by use of adenoviral vectors expressing constitutively active Akt or Hsp90. Binding of deguelin to Hsp90 was examined by docking analysis and by competition binding experiments with ATP-Sepharose beads. The proteasome inhibitor MG132 was used to investigate deguelin's effect on the induction of ubiquitin-mediated proteasomal degradation of HIF-1α. All statistical tests were two-sided. Results Deguelin bound to the AlP-binding pocket of Hsp90 and disrupted Hsp90 function, leading to ubiquitin-mediated degradation of HIF-1α. Administration of deguelin to xenograft-bearing mice statistically significantly decreased tumor growth by inducing apoptosis and decreasing the expression of Hsp90 client proteins, without detectable toxic effects. For example, at 15 days after the start of deguelin treatment, the volume of untreated control H1299 xenograft tumors was 798 mm³ and that of xenograft tumors treated with deguelin at 4 mg/kg was 115.9 mm³ (difference = 682.1 mm³, 95% confidence interval = 480.4 to 883.9 mm³ P<.001). Conclusions The antitumor activities of deguelin appear to involve its binding to the ATP-binding pocket of Hsp90, which suppresses Hsp90 function. [ABSTRACT FROM AUTHOR]

Tobacco carcinogens induce Akt activation and lung carcinogenesis. We previously demonstrated that deguelin, a natural plant product, specifically inhibits the proliferation of premalignant and malignant human bronchial epithelial cells by blocking Akt activation. To evaluate the ability of deguelin to block tobacco carcinogen-induced lung tumorigenesis, we evaluated the in vivo effects of deguelin on Akt activation and lung tumorigenesis in transgenic mice in which Akt expression was induced by tamoxifen and in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a) pyrene (BaP)-treated A/J mice. Deguelin suppressed Akt activation in vivo, as measured by immunohistochemistry and immunoblotting, and statistically significantly reduced NNK/BaP-induced lung tumor multiplicity, volume, and load in A/J mice, as monitored by microcomputed tomography image analysis, with no detectable toxicity. These results indicate that deguelin warrants consideration as a chemopreventive agent for early-stage lung carcinogenesis in a clinical lung cancer chemoprevention trial. [ABSTRACT FROM AUTHOR]

Background: The farnesyltransferase inhibitor SCH66336, in combination with other receptor tyrosine kinase inhibitors, inhibits the growth of non-small-cell lung cancer (NSCLC) cells. We examined whether SCH66336 inhibits angiogenesis of aerodigestive tract cancer cells. Methods: Antiangiogenic activities of SCH66336 against NSCLC, head and neck squamous cell carcinoma (HNSCC), and endothelial cells were examined with cell proliferation, capillary tube formation, and chick aorta (under hypoxic, normoxic, insulin-like growth factor I (IGF)-stimulated, and unstimulated conditions); reverse transcription-polymerase chain reaction; and western blot analyses. The specific roles of the ubiquitin-mediated proteasome machinery, mitogen-activated protein kinase (MAPK) and Akt pathways, and heat shock protein 90 (Hsp90) in the SCH66336-mediated degradation of hypoxia-inducible factor 1α (HIF-1α) were assessed with ubiquitin inhibitors and adenoviral vectors that express constitutively active MAP kinase kinase (MEK)1, constitutively active Akt, or Hsp90. Results: SCH66336 showed antiangiogenic activities and decreased the expression of vascular endothelial cell growth factor (VEGF) and HIF-1α in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1α protein, and ubiquitin inhibitors protected the hypoxia- or IGF-stimulated HIF-1α protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1α and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1α expression in IGF-stimulated or hypoxic cells but not in unstimulated cells. Conclusions: SCH66336 appears to inhibit angiogenic activities of NSCLC and HNSCC cells by decreasing hypoxia- or IGF-stimulated HIF-1α expression and to inhibit VEGF production by inhibiting the interaction between HIF-1α and Hsp90, resulting in the proteasomal degradation of HIF-1α. [ABSTRACT FROM AUTHOR]