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Diallyl trisulfide inhibits angiogenic features of human umbilical vein endothelial cells by causing Akt inactivation and down-regulation of VEGF and VEGF-R2.
Nutr Cancer. 2006; 55(1):94-107.NC

Abstract

We have shown recently that diallyl trisulfide (DATS), a cancer-chemopreventive constituent of garlic, inactivates Akt to trigger mitochondrial translocation of proapoptotic protein BAD in human prostate cancer cells. Because Akt activation is implicated in the promotion of endothelial cell survival and angiogenesis, we hypothesized that DATS may inhibit angiogenesis. In the present study, we tested this hypothesis using human umbilical vein endothelial cells (HUVECs) as a model. Survival of HUVECs was reduced significantly in the presence of DATS in a concentration-dependent manner, with an IC50 of approximately 4 microM. The DATS-mediated suppression of HUVEC survival was associated with apoptosis induction characterized by accumulation of subdiploid cells, cytoplasmic histone-associated DNA fragmentation, and cleavage of caspase-3 and poly-(ADP-ribose)-polymerase. The DATS-induced DNA fragmentation was significantly attenuated in the presence of pan-caspase inhibitor zVAD-fmk and specific inhibitors of caspase-9 (zLEHD-fmk) and caspase-8 (zIETD-fmk). DATS treatment inhibited the formation of capillary-like tube structure and migration by HUVECs in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level and inactivation of Akt kinase. DATS treatment also caused activation of extracellular signal-regulated kinase 1/2 (ERK1/2) but not c-Jun NH2-terminal kinase (JNK) or p38 mitogen-activated protein kinase (p38MAPK).DATS-mediatedapoptosis induction and inhibition of HUVEC tube formation was partially but statistically significantly attenuated by pharmacologic inhibition of ERK1/2 but not JNK or p38MAPK. The present study demonstrates, for the first time, that DATS has the ability to inhibit angiogenic features of human endothelial cells.

Authors+Show Affiliations

University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16965246

Citation

Xiao, Dong, et al. "Diallyl Trisulfide Inhibits Angiogenic Features of Human Umbilical Vein Endothelial Cells By Causing Akt Inactivation and Down-regulation of VEGF and VEGF-R2." Nutrition and Cancer, vol. 55, no. 1, 2006, pp. 94-107.
Xiao D, Li M, Herman-Antosiewicz A, et al. Diallyl trisulfide inhibits angiogenic features of human umbilical vein endothelial cells by causing Akt inactivation and down-regulation of VEGF and VEGF-R2. Nutr Cancer. 2006;55(1):94-107.
Xiao, D., Li, M., Herman-Antosiewicz, A., Antosiewicz, J., Xiao, H., Lew, K. L., Zeng, Y., Marynowski, S. W., & Singh, S. V. (2006). Diallyl trisulfide inhibits angiogenic features of human umbilical vein endothelial cells by causing Akt inactivation and down-regulation of VEGF and VEGF-R2. Nutrition and Cancer, 55(1), 94-107.
Xiao D, et al. Diallyl Trisulfide Inhibits Angiogenic Features of Human Umbilical Vein Endothelial Cells By Causing Akt Inactivation and Down-regulation of VEGF and VEGF-R2. Nutr Cancer. 2006;55(1):94-107. PubMed PMID: 16965246.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diallyl trisulfide inhibits angiogenic features of human umbilical vein endothelial cells by causing Akt inactivation and down-regulation of VEGF and VEGF-R2. AU - Xiao,Dong, AU - Li,Mengfeng, AU - Herman-Antosiewicz,Anna, AU - Antosiewicz,Jedrzej, AU - Xiao,Hui, AU - Lew,Karen L, AU - Zeng,Yan, AU - Marynowski,Stanley W, AU - Singh,Shivendra V, PY - 2006/9/13/pubmed PY - 2007/1/17/medline PY - 2006/9/13/entrez SP - 94 EP - 107 JF - Nutrition and cancer JO - Nutr Cancer VL - 55 IS - 1 N2 - We have shown recently that diallyl trisulfide (DATS), a cancer-chemopreventive constituent of garlic, inactivates Akt to trigger mitochondrial translocation of proapoptotic protein BAD in human prostate cancer cells. Because Akt activation is implicated in the promotion of endothelial cell survival and angiogenesis, we hypothesized that DATS may inhibit angiogenesis. In the present study, we tested this hypothesis using human umbilical vein endothelial cells (HUVECs) as a model. Survival of HUVECs was reduced significantly in the presence of DATS in a concentration-dependent manner, with an IC50 of approximately 4 microM. The DATS-mediated suppression of HUVEC survival was associated with apoptosis induction characterized by accumulation of subdiploid cells, cytoplasmic histone-associated DNA fragmentation, and cleavage of caspase-3 and poly-(ADP-ribose)-polymerase. The DATS-induced DNA fragmentation was significantly attenuated in the presence of pan-caspase inhibitor zVAD-fmk and specific inhibitors of caspase-9 (zLEHD-fmk) and caspase-8 (zIETD-fmk). DATS treatment inhibited the formation of capillary-like tube structure and migration by HUVECs in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level and inactivation of Akt kinase. DATS treatment also caused activation of extracellular signal-regulated kinase 1/2 (ERK1/2) but not c-Jun NH2-terminal kinase (JNK) or p38 mitogen-activated protein kinase (p38MAPK).DATS-mediatedapoptosis induction and inhibition of HUVEC tube formation was partially but statistically significantly attenuated by pharmacologic inhibition of ERK1/2 but not JNK or p38MAPK. The present study demonstrates, for the first time, that DATS has the ability to inhibit angiogenic features of human endothelial cells. SN - 0163-5581 UR - https://www.unboundmedicine.com/medline/citation/16965246/Diallyl_trisulfide_inhibits_angiogenic_features_of_human_umbilical_vein_endothelial_cells_by_causing_Akt_inactivation_and_down_regulation_of_VEGF_and_VEGF_R2_ L2 - http://www.tandfonline.com/doi/full/10.1207/s15327914nc5501_12 DB - PRIME DP - Unbound Medicine ER -