EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation. Export

@article{citeulike:5921059, abstract = {PURPOSE: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX), a novel Mcl-1 targeting drug. EXPERIMENTAL DESIGN: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe. RESULTS: EPOX induced endothelial cell apoptosis in association with proteasome-dependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1-free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation of Mcl-1 at T(163.) Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability. CONCLUSIONS: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesis-related pathologies.}, author = {Sun, Hui-Lung L. and Tsai, An-Chi C. and Pan, Shiow-Lin L. and Ding, Qingqing and Yamaguchi, Hirohito and Lin, Chun-Nan N. and Hung, Mien-Chie C. and Teng, Che-Ming M.}, citeulike-article-id = {5921059}, citeulike-linkout-0 = {http://dx.doi.org/10.1158/1078-0432.CCR-09-0269}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19622586}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19622586}, day = {1}, doi = {10.1158/1078-0432.CCR-09-0269}, issn = {1078-0432}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, keywords = {angiogenesis, apoptosis, erk, gsh, herb, ros, tw}, month = {August}, number = {15}, pages = {4904--4914}, posted-at = {2009-10-11 13:24:22}, priority = {2}, title = {EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation.}, url = {http://dx.doi.org/10.1158/1078-0432.CCR-09-0269}, volume = {15}, year = {2009} }

TY - JOUR ID - citeulike:5921059 L3 - citeulike-article-id:5921059 N2 - PURPOSE: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX), a novel Mcl-1 targeting drug. EXPERIMENTAL DESIGN: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe. RESULTS: EPOX induced endothelial cell apoptosis in association with proteasome-dependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1-free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation of Mcl-1 at T(163.) Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability. CONCLUSIONS: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesis-related pathologies. IS - 15 JF - Clinical cancer research : an official journal of the American Association for Cancer Research SN - 1078-0432 EP - 4914 TI - EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation. VL - 15 SP - 4904 KW - angiogenesis KW - apoptosis KW - erk KW - gsh KW - herb KW - ros KW - tw AU - Sun, Hui-Lung AU - Tsai, An-Chi AU - Pan, Shiow-Lin AU - Ding, Qingqing AU - Yamaguchi, Hirohito AU - Lin, Chun-Nan AU - Hung, Mien-Chie AU - Teng, Che-Ming PY - 2009/08/01/ UR - http://dx.doi.org/10.1158/1078-0432.CCR-09-0269 ER -