Title

 

Authors

*R. Minelli, ‡ P. Pettazzoni, *L. Serpe, ‡G. Barrera, *R. Fantozzi, *GP. Zara and *C. Dianzani
 

* Department of Anatomy, Pharmacology and Forensic Medicine, University of Torino, Torino, Italy.
‡ Department of Medicine and Experimental Oncology, Section of General Pathology, University of Torino, Torino, Italy.

 

Abstract

Cholesteryl butyrate solid lipid nanoparticles (cholbut SLN) can be a delivery system [1] for the anti-cancer drug butyrate which acts as a Histone Deacetylase Inhibitor(HDACI). Wepreviously showed that cholbut SLN inhibit adhesion of polymorphonuclear cells (PMNs) to human umbilical vein endothelial cells (HUVEC) and suggested that they may act as an anti-inflammatory agent [2]. Since cancer cell adhesion to endothelial cells is crucial for metastasis dissemination and uses similar adhesion mechanisms as PMNs, aim of this work was to evaluate the effect of cholbut SLN on adhesion and migration of tumour cell lines, mainly focusing on colon rectal carcinoma. We found that cholbut SLN inhibited HUVEC adhesiveness to tumour cell lines from colon rectum (HT29, HCT116, CaCo-2), breast (MFC-7), prostate (PC-3) and melanoma (M14 and LM). The effect was dependent on the cholbut SLN concentration in the 0.1-100 µM range, detectable as soon as 8 h after the treatment, still present after 48 h, and exerted on both tumour cells and HUVEC. Moreover starting from the 10 µM dose, treatment with cholbut SLNalso inhibited migration of these cell lines as detected by the scratch ”wound healing” assay and the Boyden chamber invasion assay. Cholbut SLN treatment did not modulate expression of adhesion molecules, but substantially down-modulated ERK and p38 phosphorylation induced by VEGF-A in HUVEC, and ERK phosphorylation induced by PMA in HT29. The cholbut SLN anti-adhesive effect was additive to that induced by triggering of B7h, which can also inhibit signaling through ERK and p38 [3]. Furthermore, cholbut SLN induced E-cadherin and inhibited claudin-1 expression in HUVEC. These results provided evidence for a role of cholbut SLN as an anti-metastastic drug. This anti-tumor effect was partly different from that displayed by sodium butyrate (Nabut), which inhibited tumour cell adhesion only over the 100 µM dose and did not inhibit migration. Moreover, Nabutdisplayed a strong HDACI activity that was absent in our cholbut SLN preparations.
1) Manjunath K; Reddy JS; Venkateswarlu V. (2005) Solid lipid nanoparticles as drug delivery systems. Methods Find.Exp. Clin. Pharmacol. 27: 127–144.
2) Dianzani C; Cavalli R; Zara GP; Gallicchio M; Lombardi G; Gasco MR; Panzanelli P; Fantozzi R. (2006) Cholesteryl butyrate solid lipid nanoparticles inhibit adhesion of human neutrophils to endothelial cells. Br J Pharmacol. 148: 648-656.
3) Dianzani C; Minelli R; Mesturini R; Chiocchetti A; Barrera G; Boscolo S; Sarasso C; Gigliotti CL; Sblattero D; Yagi J; Rojo JM; Fantozzi R; Dianzani U. (2010) B7h triggering inhibits umbelical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells. J Immunol. 185: 3970-3979.