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Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1α/vascular endothelial growth factor expression via inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma cells.

Wang F, Zhang W, Guo L, Bao W, Jin N, Liu R, Liu P, Wang Y, Guo Q, Chen B - Cancer Sci. (2014)

Bottom Line: We found that hypoxia induced increase in the level of HIF-1α subunit protein and activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target protein of rapamycin (mTOR) pathway.Mechanistic studies exhibited that GA inhibited the production of HIF-1α by reducing phosphorylation of Akt and mTOR in U266 cells.Taken together, our results identify that GA suppresses hypoxia-activated pathways that are linked to MM progression, at least partly, by the inhibition of the PI3K/Akt/mTOR signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, China.

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Related in: MedlinePlus

Gambogic acid (GA) inhibited tumor angiogenesis in U266 xenograft mouse model. (a) Immunohistochemistry was performed in tumor sections with antibodies of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD31. The result showed a remarkable decrease in expression of HIF-1α, VEGF and CD31 in the treated groups with 2 and 4 mg/kg GA compared with untreated control groups. (b) To identify the tumor angiogenesis, the stained area of CD31 in 10 fields was quantified by using Image Pro Plus. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01. (c) The images were quantified using Image Pro Plus and mean optical densities (of control) of VEGF and HIF-1α were shown. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01.
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fig06: Gambogic acid (GA) inhibited tumor angiogenesis in U266 xenograft mouse model. (a) Immunohistochemistry was performed in tumor sections with antibodies of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD31. The result showed a remarkable decrease in expression of HIF-1α, VEGF and CD31 in the treated groups with 2 and 4 mg/kg GA compared with untreated control groups. (b) To identify the tumor angiogenesis, the stained area of CD31 in 10 fields was quantified by using Image Pro Plus. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01. (c) The images were quantified using Image Pro Plus and mean optical densities (of control) of VEGF and HIF-1α were shown. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01.

Mentions: To confirm the macroscopic observations and address the potential effect of GA in vivo, immunohistochemistry was performed. The results showed that the presence of endothelial-specific antibody CD31-stained capillaries in xenografts was dose-dependently reduced by GA treatment (Fig. 6a,b), suggesting GA attenuated the tumor angiogenesis. To investigate whether the anti-angiogenesis effect of GA was due to the decreased level of VEGF and HIF-1α, immunohistochemistry for VEGF and HIF-1α was performed. The same as CD31, the tumor sections treated with GA showed significantly lower levels of VEGF and HIF-1α than that of control tumor tissue (Fig. 6a,c). These results further supported that GA, a HIF-1α inhibitor, is a potential compound for MM therapy.


Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1α/vascular endothelial growth factor expression via inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma cells.

Wang F, Zhang W, Guo L, Bao W, Jin N, Liu R, Liu P, Wang Y, Guo Q, Chen B - Cancer Sci. (2014)

Gambogic acid (GA) inhibited tumor angiogenesis in U266 xenograft mouse model. (a) Immunohistochemistry was performed in tumor sections with antibodies of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD31. The result showed a remarkable decrease in expression of HIF-1α, VEGF and CD31 in the treated groups with 2 and 4 mg/kg GA compared with untreated control groups. (b) To identify the tumor angiogenesis, the stained area of CD31 in 10 fields was quantified by using Image Pro Plus. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01. (c) The images were quantified using Image Pro Plus and mean optical densities (of control) of VEGF and HIF-1α were shown. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317858&req=5

fig06: Gambogic acid (GA) inhibited tumor angiogenesis in U266 xenograft mouse model. (a) Immunohistochemistry was performed in tumor sections with antibodies of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD31. The result showed a remarkable decrease in expression of HIF-1α, VEGF and CD31 in the treated groups with 2 and 4 mg/kg GA compared with untreated control groups. (b) To identify the tumor angiogenesis, the stained area of CD31 in 10 fields was quantified by using Image Pro Plus. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01. (c) The images were quantified using Image Pro Plus and mean optical densities (of control) of VEGF and HIF-1α were shown. Bars are the mean ± SD (n = 10). The comparisons were made relative to untreated controls, and the different levels of significance was indicated as **P < 0.01.
Mentions: To confirm the macroscopic observations and address the potential effect of GA in vivo, immunohistochemistry was performed. The results showed that the presence of endothelial-specific antibody CD31-stained capillaries in xenografts was dose-dependently reduced by GA treatment (Fig. 6a,b), suggesting GA attenuated the tumor angiogenesis. To investigate whether the anti-angiogenesis effect of GA was due to the decreased level of VEGF and HIF-1α, immunohistochemistry for VEGF and HIF-1α was performed. The same as CD31, the tumor sections treated with GA showed significantly lower levels of VEGF and HIF-1α than that of control tumor tissue (Fig. 6a,c). These results further supported that GA, a HIF-1α inhibitor, is a potential compound for MM therapy.

Bottom Line: We found that hypoxia induced increase in the level of HIF-1α subunit protein and activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target protein of rapamycin (mTOR) pathway.Mechanistic studies exhibited that GA inhibited the production of HIF-1α by reducing phosphorylation of Akt and mTOR in U266 cells.Taken together, our results identify that GA suppresses hypoxia-activated pathways that are linked to MM progression, at least partly, by the inhibition of the PI3K/Akt/mTOR signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, China.

Show MeSH
Related in: MedlinePlus