Aims. The aims of this study were to evaluate the antitumor and antiangiogenic activity of metronomic ceramide analogs and to investigate their relevant molecular mechanisms. Methods. Human endothelial cells (HMVEC-d, HUVEC) and pancreatic cancer cells (Capan-1, MIAPaCa-2) were treated with the ceramide analogs (C2, AL6, C6 and C8), at low concentrations for 144h to evaluate any antiproliferative and pro-apoptotic effects, inhibition of migration, and to measure the expression of caveolin-1 (CAV-1) and thrombospondin-1 (TSP-1) mRNAs by real time RT-PCR. Assessment of ERK1/2 and Akt phosphorylation, and of CAV-1 and cyclin-D1 protein expression was performed by ELISA. Maximum tolerated dose (MTD) gemcitabine was compared against metronomic doses of the ceramide analogs by evaluating the inhibition of MIAPaCA-2 subcutaneous tumor growth in nude mice. Results. Metronomic ceramide analogs preferentially inhibited cell proliferation and enhanced apoptosis in endothelial cells. Low concentrations of AL6 and C2 caused a significant inhibition of HUVEC cell migration. ERK1/2 and Akt phosphorylation were significantly decreased after metronomic ceramide analog treatment. Such treatment caused the over-expression of CAV-1 and TSP-1 mRNA and protein in endothelial cells, whereas cyclin-D1 protein levels were reduced significantly. The antiangiogenic and antitumor impact in vivo of metronomic C2 and AL6 regimens was similar to that caused by MTD gemcitabine. C6 and C8 did not show any significant in vivo antitumor effects. Conclusions. Metronomic C2 and AL6 analogs have antitumor and antiangiogenic activity, determining the upregulation of CAV-1 and TSP-1 and the suppression of cyclin-D1.
|Autori:||Bocci G; Fioravanti A; Orlandi P; Di Desidero T; Natale G; Fanelli G; Viacava P; Naccarato AG; Francia G; Danesi R.|
|Titolo:||Metronomic ceramide analogs inhibit angiogenesis in pancreatic cancer through up-regulation of caveolin-1 and thrombospondin-1 and down-regulation of cyclin D1|
|Anno del prodotto:||2012|
|Digital Object Identifier (DOI):||10.1593/neo.12772|
|Appare nelle tipologie:||1.1 Articolo in rivista|