Inhibition of Kaposi's sarcoma in vivo by fenretinide

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.(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.In vivo, 4HPR significantly (P0.001) reduced growth of detectable Kaposi's sarcoma (KS) xenografts and inhibited angiogenesis in the Matrigel plug assay (P0.04). 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.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.