PURPOSE: We examined the effects of fenretinide [N-(4-hydroxyphenyl)retinamide; (4HPR)] on highly angiogenic Kaposi's sarcoma tumors in vivo and investigated the mechanisms involved for potential clinical applications. EXPERIMENTAL DESIGN: (CD-1)BR nude mice bearing KS-Imm cell tumors were randomized to receive 4HPR or vehicle until sacrifice. In vitro, KS-Imm and endothelial cells were treated with 4HPR to study the effects on proliferation, apoptosis, migration, and invasion; in vivo angiogenesis was evaluated in the Matrigel model. Angiogenesis-related and retinoid receptor molecules were examined at the mRNA and protein expression levels. RESULTS: In vivo, 4HPR significantly (P<0.001) reduced growth of detectable Kaposi's sarcoma (KS) xenografts and inhibited angiogenesis in the Matrigel plug assay (P<0.04). In vitro, 4HPR affected KS-Imm and endothelial cell growth and KS-Imm migration and invasion. 4HPR invasion inhibition was associated with decreased release of matrix metalloprotease-2 and rapid reduction of vascular endothelial growth factor (VEGF) expression by KS cells and of vascular endothelial growth factor receptor 2 (VEGFR2) by KS and endothelial cells. Finally, 4HPR repression of angiogenesis was associated with a 4HPR-induced increase in retinoic acid receptor beta expression. CONCLUSIONS: These data indicate that 4HPR inhibits KS tumor growth in vivo through a mechanism involving the modulation of angiogenesis-associated growth factors and their receptors on both tumor and endothelial cells. In addition, 4HPR inhibited invasion by decreasing of matrix metalloprotease-2 activity. Our results justify further studies to evaluate the utility of 4HPR as a chemopreventive or therapeutic agent in KS, a malignancy associated with immune suppression that has a high risk of recurrence with highly active antiretroviral therapy failure.
PURPOSE: We examined the effects of fenretinide [N-(4-hydroxyphenyl)retinamide; (4HPR)] on highly angiogenic Kaposi's sarcoma tumors in vivo and investigated the mechanisms involved for potential clinical applications. EXPERIMENTAL DESIGN: (CD-1)BR nude mice bearing KS-Imm cell tumors were randomized to receive 4HPR or vehicle until sacrifice. In vitro, KS-Imm and endothelial cells were treated with 4HPR to study the effects on proliferation, apoptosis, migration, and invasion; in vivo angiogenesis was evaluated in the Matrigel model. Angiogenesis-related and retinoid receptor molecules were examined at the mRNA and protein expression levels. RESULTS: In vivo, 4HPR significantly (P<0.001) reduced growth of detectable Kaposi's sarcoma (KS) xenografts and inhibited angiogenesis in the Matrigel plug assay (P<0.04). In vitro, 4HPR affected KS-Imm and endothelial cell growth and KS-Imm migration and invasion. 4HPR invasion inhibition was associated with decreased release of matrix metalloprotease-2 and rapid reduction of vascular endothelial growth factor (VEGF) expression by KS cells and of vascular endothelial growth factor receptor 2 (VEGFR2) by KS and endothelial cells. Finally, 4HPR repression of angiogenesis was associated with a 4HPR-induced increase in retinoic acid receptor beta expression. CONCLUSIONS: These data indicate that 4HPR inhibits KS tumor growth in vivo through a mechanism involving the modulation of angiogenesis-associated growth factors and their receptors on both tumor and endothelial cells. In addition, 4HPR inhibited invasion by decreasing of matrix metalloprotease-2 activity. Our results justify further studies to evaluate the utility of 4HPR as a chemopreventive or therapeutic agent in KS, a malignancy associated with immune suppression that has a high risk of recurrence with highly active antiretroviral therapy failure.
Authors: Dong-Wan Seo; W Carl Saxinger; Liliana Guedez; Anna Rita Cantelmo; Adriana Albini; William G Stetler-Stevenson Journal: Peptides Date: 2011-08-16 Impact factor: 3.750
Authors: Byungdo B Han; Suyang Li; Meng Tong; Andrew S Holpuch; Richard Spinney; Daren Wang; Michael B Border; Zhongfa Liu; Sachin Sarode; Ping Pei; Steven P Schwendeman; Susan R Mallery Journal: Cancer Prev Res (Phila) Date: 2015-02-24