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Waun Ki Hong - One of the best experts on this subject based on the ideXlab platform.
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Effects of Insulin-like Growth Factor Binding Protein-3 and Farnesyltransferase Inhibitor SCH66336 on Akt Expression and Apoptosis in Non–Small-Cell Lung Cancer Cells
2013Co-Authors: Hoyoung Lee, Kyung Hee Chun, Fadlo R Khuri, Reuben Lotan, Hojin Moon, Yoon Soo Chang, Waun Ki HongAbstract:binding protein-3 (IGFBP-3) induces apoptosis in non– small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a Farnesyltransferase Inhibitor that blocks Ras activation, in NSCLC cell lines. Methods: The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry–based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis. Results: The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels. Conclusions: The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo
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hypoxia inducible factor 1α and antiangiogenic activity of Farnesyltransferase Inhibitor sch66336 in human aerodigestive tract cancer
Journal of the National Cancer Institute, 2005Co-Authors: Ji Youn Han, Waun Ki Hong, Edward S Kim, F Morgillo, Jeffrey N Myers, Hoyoung LeeAbstract: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 1alpha (HIF-1alpha) 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-1alpha in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1alpha protein, and ubiquitin Inhibitors protected the hypoxia- or IGF-stimulated HIF-1alpha protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1alpha and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1alpha 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-1alpha expression and to inhibit VEGF production by inhibiting the interaction between HIF-1alpha and Hsp90, resulting in the proteasomal degradation of HIF-1alpha.
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effects of insulin like growth factor binding protein 3 and Farnesyltransferase Inhibitor sch66336 on akt expression and apoptosis in non small cell lung cancer cells
Journal of the National Cancer Institute, 2004Co-Authors: Hoyoung Lee, Kyung Hee Chun, Khaled A Hassan, Fadlo R Khuri, Reuben Lotan, Hojin Moon, Yoon Soo Chang, Waun Ki HongAbstract:Background: Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) induces apoptosis in non‐ small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a Farnesyltransferase Inhibitor that blocks Ras activation, in NSCLC cell lines. Methods: The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry‐based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis. Results: The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels. Conclusions: The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo. Simultaneous treatment with IGFBP-3 and SCH66336 may have the potential to be an effective therapeutic strategy in NSCLC. [J Natl Cancer Inst 2004;96:1536‐48]
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implication of protein kinase b akt and bcl 2 bcl xl suppression by the farnesyl transferase Inhibitor sch66336 in apoptosis induction in squamous carcinoma cells
Cancer Research, 2003Co-Authors: Kyung Hee Chun, Hoyoung Lee, Khaled A Hassan, Fadlo R Khuri, Waun Ki Hong, Reuben LotanAbstract:The Farnesyltransferase Inhibitor SCH66336 exhibits antitumor activity in vitro and in vivo; however, its mechanism of action is still unresolved. We found that SCH66336 suppressed growth and induced apoptosis of human head and neck squamous carcinoma cells (HNSCC). SCH66336 suppressed protein kinase B/Akt activity as well as the phosphorylation of the Akt substrates glycogen synthase kinase (GSK)-3β, forkhead transcription factor, and BAD. Infection of SqCC/Y1 cells with an adenovirus that contained a constitutively active form of Akt rescued cells from SCH66336-induced apoptosis. These results suggest that SCH66336 is a potent apoptosis inducer in HNSCC cells and that it may act by suppressing the Akt pathway.
Hoyoung Lee - One of the best experts on this subject based on the ideXlab platform.
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Effects of Insulin-like Growth Factor Binding Protein-3 and Farnesyltransferase Inhibitor SCH66336 on Akt Expression and Apoptosis in Non–Small-Cell Lung Cancer Cells
2013Co-Authors: Hoyoung Lee, Kyung Hee Chun, Fadlo R Khuri, Reuben Lotan, Hojin Moon, Yoon Soo Chang, Waun Ki HongAbstract:binding protein-3 (IGFBP-3) induces apoptosis in non– small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a Farnesyltransferase Inhibitor that blocks Ras activation, in NSCLC cell lines. Methods: The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry–based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis. Results: The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels. Conclusions: The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo
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hypoxia inducible factor 1α and antiangiogenic activity of Farnesyltransferase Inhibitor sch66336 in human aerodigestive tract cancer
Journal of the National Cancer Institute, 2005Co-Authors: Ji Youn Han, Waun Ki Hong, Edward S Kim, F Morgillo, Jeffrey N Myers, Hoyoung LeeAbstract: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 1alpha (HIF-1alpha) 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-1alpha in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1alpha protein, and ubiquitin Inhibitors protected the hypoxia- or IGF-stimulated HIF-1alpha protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1alpha and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1alpha 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-1alpha expression and to inhibit VEGF production by inhibiting the interaction between HIF-1alpha and Hsp90, resulting in the proteasomal degradation of HIF-1alpha.
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effects of insulin like growth factor binding protein 3 and Farnesyltransferase Inhibitor sch66336 on akt expression and apoptosis in non small cell lung cancer cells
Journal of the National Cancer Institute, 2004Co-Authors: Hoyoung Lee, Kyung Hee Chun, Khaled A Hassan, Fadlo R Khuri, Reuben Lotan, Hojin Moon, Yoon Soo Chang, Waun Ki HongAbstract:Background: Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) induces apoptosis in non‐ small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a Farnesyltransferase Inhibitor that blocks Ras activation, in NSCLC cell lines. Methods: The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry‐based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis. Results: The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels. Conclusions: The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo. Simultaneous treatment with IGFBP-3 and SCH66336 may have the potential to be an effective therapeutic strategy in NSCLC. [J Natl Cancer Inst 2004;96:1536‐48]
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implication of protein kinase b akt and bcl 2 bcl xl suppression by the farnesyl transferase Inhibitor sch66336 in apoptosis induction in squamous carcinoma cells
Cancer Research, 2003Co-Authors: Kyung Hee Chun, Hoyoung Lee, Khaled A Hassan, Fadlo R Khuri, Waun Ki Hong, Reuben LotanAbstract:The Farnesyltransferase Inhibitor SCH66336 exhibits antitumor activity in vitro and in vivo; however, its mechanism of action is still unresolved. We found that SCH66336 suppressed growth and induced apoptosis of human head and neck squamous carcinoma cells (HNSCC). SCH66336 suppressed protein kinase B/Akt activity as well as the phosphorylation of the Akt substrates glycogen synthase kinase (GSK)-3β, forkhead transcription factor, and BAD. Infection of SqCC/Y1 cells with an adenovirus that contained a constitutively active form of Akt rescued cells from SCH66336-induced apoptosis. These results suggest that SCH66336 is a potent apoptosis inducer in HNSCC cells and that it may act by suppressing the Akt pathway.
Stephen G. Young - One of the best experts on this subject based on the ideXlab platform.
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Targeting Protein Prenylation in Progeria
Science translational medicine, 2013Co-Authors: Stephen G. Young, Shao H. Yang, Brandon S. J. Davies, Hea-jin JungAbstract:A clinical trial of a protein Farnesyltransferase Inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein Farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.
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treatment with a Farnesyltransferase Inhibitor improves survival in mice with a hutchinson gilford progeria syndrome mutation
Biochimica et Biophysica Acta, 2008Co-Authors: Shao H. Yang, Xin Qiao, Stephen G. YoungAbstract:Summary Hutchinson-Gilford progeria syndrome (HGPS) is a progeroid syndrome characterized by multiple aging-like disease phenotypes. We recently reported that a protein Farnesyltransferase Inhibitor (FTI) improved several disease phenotypes in mice with a HGPS mutation (Lmna HG/+ ). Here, we investigated the impact of an FTI on the survival of Lmna HG/+ mice. The FTI significantly improved the survival of both male and female Lmna HG/+ mice. Treatment with the FTI also improved body weight curves and reduced the number of spontaneous rib fractures. This study provides further evidence for a beneficial effect of an FTI in HGPS.
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Prelamin A farnesylation and progeroid syndromes.
The Journal of biological chemistry, 2006Co-Authors: Stephen G. Young, Margarita Meta, Loren G. FongAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation that leads to the synthesis of a mutant prelamin A that is farnesylated but cannot be further processed to mature lamin A. A more severe progeroid disorder, restrictive dermopathy (RD), is caused by the loss of the prelamin A-processing enzyme, ZMPSTE24. The absence of ZMPSTE24 prevents the endoproteolytic processing of farnesyl-prelamin A to mature lamin A and leads to the accumulation of farnesyl-prelamin A. In both HGPS and RD, the farnesyl-prelamin A is targeted to the nuclear envelope, where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei. Recent studies have shown that the frequency of misshapen nuclei can be reduced by treating cells with a Farnesyltransferase Inhibitor (FTI). Also, administering an FTI to mouse models of HGPS and RD ameliorates the phenotypes of progeria. These studies have prompted interest in testing the efficacy of FTIs in children with HGPS.
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a Farnesyltransferase Inhibitor improves disease phenotypes in mice with a hutchinson gilford progeria syndrome mutation
Journal of Clinical Investigation, 2006Co-Authors: Shao H. Yang, Xin Qiao, Stephen G. Young, Catherine Coffinier, David J. Frost, Margarita Meta, Martin O Bergo, Joy Bauch, Sharmila Majumdar, Loren G. FongAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus. Progerin is targeted to the nuclear envelope and causes misshapen nuclei. Protein Farnesyltransferase Inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the frequency of misshapen nuclei. To determine whether an FTI would ameliorate disease phenotypes in vivo, we created gene-targeted mice with an HGPS mutation (LmnaHG/+) and then examined the effect of an FTI on disease phenotypes. LmnaHG/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. Osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness. These studies suggest that FTIs could be useful for treating humans with HGPS.
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A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria
Science (New York N.Y.), 2006Co-Authors: David J. Frost, Shao H. Yang, Xin Qiao, Catherine Coffinier, Margarita Meta, Stephen G. YoungAbstract:Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl–prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that Farnesyltransferase Inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24 -deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.
Edo Vellenga - One of the best experts on this subject based on the ideXlab platform.
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combining simvastatin with the Farnesyltransferase Inhibitor tipifarnib results in an enhanced cytotoxic effect in a subset of primary cd34 acute myeloid leukemia samples
Clinical Cancer Research, 2009Co-Authors: Karen Van Der Weide, Folkert Kuipers, Elisabeth G. E. Devries, Susan D P W M De Jongepeeters, Edo VellengaAbstract:Purpose: To show whether the Inhibitory effects of the cholesterol synthesis Inhibitor simvastatin on human CD34 + acute myeloid leukemia (AML) cells can be further promoted by combining it with the Farnesyltransferase Inhibitor tipifarnib. Experimental Design: Normal CD34 + , AML CD34 + , and CD34 − sorted subfractions, and AML cell lines (TF-1 and KG1A) were exposed to simvastatin and tipifarnib. Results: Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34 + AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal ( n = 12) and abnormal ( n = 10) responders were identified within the AML CD34 + subfraction when compared with normal CD34 + cells. This distinction was not observed within the AML CD34 − cell fraction. When the CD34 + AML cells were exposed to simvastatin and tipifarnib, a significant enhanced Inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34 − cell fractions all showed an enhanced Inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment. Conclusion: The results suggest that combined treatment with statins and Farnesyltransferase Inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34 + fraction.
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Combining Simvastatin with the Farnesyltransferase Inhibitor Tipifarnib Results in an Enhanced Cytotoxic Effect in a Subset of Primary CD34(+) Acute Myeloid Leukemia Samples
Clinical cancer research : an official journal of the American Association for Cancer Research, 2009Co-Authors: Karen Van Der Weide, Susan D. P. W. M. De Jonge-peeters, Folkert Kuipers, Elisabeth G. E. Devries, Edo VellengaAbstract:Purpose: To show whether the Inhibitory effects of the cholesterol synthesis Inhibitor simvastatin on human CD34 + acute myeloid leukemia (AML) cells can be further promoted by combining it with the Farnesyltransferase Inhibitor tipifarnib. Experimental Design: Normal CD34 + , AML CD34 + , and CD34 − sorted subfractions, and AML cell lines (TF-1 and KG1A) were exposed to simvastatin and tipifarnib. Results: Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34 + AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal ( n = 12) and abnormal ( n = 10) responders were identified within the AML CD34 + subfraction when compared with normal CD34 + cells. This distinction was not observed within the AML CD34 − cell fraction. When the CD34 + AML cells were exposed to simvastatin and tipifarnib, a significant enhanced Inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34 − cell fractions all showed an enhanced Inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment. Conclusion: The results suggest that combined treatment with statins and Farnesyltransferase Inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34 + fraction.
Fadlo R Khuri - One of the best experts on this subject based on the ideXlab platform.
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Effects of Insulin-like Growth Factor Binding Protein-3 and Farnesyltransferase Inhibitor SCH66336 on Akt Expression and Apoptosis in Non–Small-Cell Lung Cancer Cells
2013Co-Authors: Hoyoung Lee, Kyung Hee Chun, Fadlo R Khuri, Reuben Lotan, Hojin Moon, Yoon Soo Chang, Waun Ki HongAbstract:binding protein-3 (IGFBP-3) induces apoptosis in non– small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a Farnesyltransferase Inhibitor that blocks Ras activation, in NSCLC cell lines. Methods: The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry–based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis. Results: The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels. Conclusions: The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo
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effects of insulin like growth factor binding protein 3 and Farnesyltransferase Inhibitor sch66336 on akt expression and apoptosis in non small cell lung cancer cells
Journal of the National Cancer Institute, 2004Co-Authors: Hoyoung Lee, Kyung Hee Chun, Khaled A Hassan, Fadlo R Khuri, Reuben Lotan, Hojin Moon, Yoon Soo Chang, Waun Ki HongAbstract:Background: Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) induces apoptosis in non‐ small-cell lung cancer (NSCLC) cells in vitro and in vivo. However, Ras-mediated signaling pathways could develop resistance to apoptotic activities of IGFBP-3 in NSCLC cells. We thus evaluated the therapeutic potential of the combination of IGFBP-3 and SCH66336, a Farnesyltransferase Inhibitor that blocks Ras activation, in NSCLC cell lines. Methods: The effects of the combination of adenoviral IGFBP-3 (Ad-IGFBP3) and SCH66336 on proliferation and apoptosis of NSCLC cell lines (H1299, H596, A549, H460, H358, H322, and H226B) were assessed in vitro and in vivo by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometry‐based terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, western blot analyses, and an NSCLC xenograft tumor model. The specific effects of Ad-IGFBP 3 and SCH66336 on mitogen-activated protein kinase and Akt were assessed by using adenoviral vectors that express constitutively active MEK1 or constitutively active Akt. Synergy was assessed by median effect analysis. Results: The combination of Ad-IGFBP3 and SCH66336 had synergistic antiproliferative effects in five cell lines (H1299, H596, A549, H460, and H322). Antiproliferative effects were accompanied by increased apoptosis in H460 cells in vitro. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. In H1299 tumor xenografts, Ad-IGFBP3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels. Conclusions: The combination of Ad-IGFBP3 and SCH66336 decreased Akt expression and increased apoptosis in NSCLC cells in vitro and in vivo. Simultaneous treatment with IGFBP-3 and SCH66336 may have the potential to be an effective therapeutic strategy in NSCLC. [J Natl Cancer Inst 2004;96:1536‐48]
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protein Farnesyltransferase Inhibitor sch 66336 abolishes nf κb activation induced by various carcinogens and inflammatory stimuli leading to suppression of nf κb regulated gene expression and up regulation of apoptosis
Journal of Biological Chemistry, 2004Co-Authors: Yasunari Takada, Fadlo R Khuri, Bharat B AggarwalAbstract:Abstract Ras Farnesyltransferase Inhibitor (FTI) exhibit antiproliferative and antiangiogenic effects through a mechanism that is poorly understood. Because of the known role of Ras in the activation of transcription factor NF-κB and because NF-κB-regulated genes can control cell survival and angiogenesis, we postulated that FTI mediates its effects in part by modulating NF-κB activation. Therefore, in the present study we investigated the effect of FTI, SCH 66336, on NF-κB and NF-κB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. We demonstrate by DNA-binding assay that NF-κB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, cigarette smoke, okadaic acid, and H2O2 was completely suppressed by SCH 66336; the suppression was not cell type-specific. This FTI suppressed the activation of IκBα kinase (IKK), thus abrogating the phosphorylation and degradation of IκBα. Additionally, TNF-activated Ras and SCH 66336 inhibited the activation. Also, overexpression of Ras (V12) enhanced TNF-induced NF-κB activation, and adenoviral dominant-negative Ras (N17) suppressed the activation, thus suggesting the critical role of Ras in TNF signaling. SCH 66336 also inhibited the NF-κB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-κB. The TNF-induced NF-κB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP1, IAP2, XIAP, Bcl-2, Bfl-1/A1, TRAF1, and FLIP were all down-regulated by SCH 66336, which potentiated apoptosis induced by TNF and doxorubicin. Overall, our results indicate that SCH 66336 inhibited activation of NF-κB and NF-κB-regulated gene expressions induced by carcinogens and inflammatory stimuli, which may provide a molecular basis for the ability of SCH 66336 to suppress proliferation and angiogenesis.
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implication of protein kinase b akt and bcl 2 bcl xl suppression by the farnesyl transferase Inhibitor sch66336 in apoptosis induction in squamous carcinoma cells
Cancer Research, 2003Co-Authors: Kyung Hee Chun, Hoyoung Lee, Khaled A Hassan, Fadlo R Khuri, Waun Ki Hong, Reuben LotanAbstract:The Farnesyltransferase Inhibitor SCH66336 exhibits antitumor activity in vitro and in vivo; however, its mechanism of action is still unresolved. We found that SCH66336 suppressed growth and induced apoptosis of human head and neck squamous carcinoma cells (HNSCC). SCH66336 suppressed protein kinase B/Akt activity as well as the phosphorylation of the Akt substrates glycogen synthase kinase (GSK)-3β, forkhead transcription factor, and BAD. Infection of SqCC/Y1 cells with an adenovirus that contained a constitutively active form of Akt rescued cells from SCH66336-induced apoptosis. These results suggest that SCH66336 is a potent apoptosis inducer in HNSCC cells and that it may act by suppressing the Akt pathway.
