Search

BACKGROUND AND PURPOSE Cholesteryl butyrate solid lipid nanoparticles (cholbut SLN) provide a delivery system for the anti-cancer drug butyrate. These SLN inhibit the adhesion of polymorphonuclear cells to the endothelium and may act as anti-inflammatory agents. As cancer cell adhesion to endothelium is crucial for metastasis dissemination, here we have evaluated the effect of cholbut SLN on adhesion and migration of cancer cells. EXPERIMENTAL APPROACH Cholbut SLN was incubated with a number of cancer cell lines or human umbilical vein endothelial cells (HUVEC) and adhesion was quantified by a computerized micro-imaging system. Migration was detected by the scratch 'wound-healing' assay and the Boyden chamber invasion assay. Expression of ERK and p38 MAPK was analysed by Western blot. Expression of the mRNA for E-cadherin and claudin-1 was measured by RT-PCR. KEY RESULTS Cholbut SLN inhibited HUVEC adhesiveness to cancer cell lines derived from human colon-rectum, breast, prostate cancers and melanoma. The effect was concentration and time-dependent and exerted on both cancer cells and HUVEC. Moreover, these SLN inhibited migration of cancer cells and substantially down-modulated ERK and p38 phosphorylation. The anti-adhesive effect was additive to that induced by the triggering of B7h, which is another stimulus inhibiting both ERK and p38 phosphorylation, and cell adhesiveness. Furthermore, cholbut SLN induced E-cadherin and inhibited claudin-1 expression in HUVEC. CONCLUSION AND IMPLICATIONS These results suggest that cholbut SLN could act as an anti-metastastic agent and they add a new mechanism to the anti-tumour activity of this multifaceted preparation of butyrate. [ABSTRACT FROM AUTHOR]

Background and Purpose Solid lipid nanoparticles containing cholesteryl butyrate (cholbut SLN) can be a delivery system for the anti-cancer drug butyrate. These nanoparticles inhibit adhesion of polymorphonuclear and tumour cells to endothelial cells and migration of tumour cells, suggesting that they may act as anti-inflammatory and anti-tumour agents. Here we have evaluated the effects of cholbut SLN on tumour cell growth using in vitro and in vivo models. Experimental Approach Cholbut SLNs were incubated with cultures of four tumour cell lines, and cell growth was analysed by assessing viability, clonogenic capacity and cell cycle. Effects on intracellular signalling was assessed by Western blot analysis of Akt expression. The in vivo anti-tumour activity was measured in two models of PC-3 cell xenografts in SCID/Beige mice. Key Results Cholbut SLN inhibited tumour cell line viability, clonogenic activity, Akt phosphorylation and cell cycle progression. In mice injected i.v. with PC3- Luc cells and treated with cholbut SLN, . in vivo optical imaging and histological analysis showed no metastases in the lungs of the treated mice. In another set of mice injected s.c. with PC-3 cells and treated with cholbut SLN when the tumour diameter reached 2 mm, analysis of the tumour dimensions showed that treatment with cholbut SLN substantially delayed tumour growth. Conclusion and Implications Cholbut SLN were effective in inhibiting tumour growth in vitro and in vivo. These effects may involve, in part, inhibition of Akt phosphorylation, which adds another mechanism to the activity of this multipotent drug. [ABSTRACT FROM AUTHOR]

Abstract Aim A case of autoimmune Type 1 diabetes with some unique characteristics developing in a 29-year-old male during treatment with interferon-alpha (IFN-α) for chronic hepatitis C virus (HCV) hepatitis is reported. Patient and methods In this patient IFN-α treatment was well tolerated and successful in the cure of hepatitis with eradication of HCV infection within 3 months, but at 8.5 months Type 1 diabetes appeared and insulin therapy was started and maintained thereafter. HLA class II molecular typing was determined and retrospective measurement of islet cell (ICA), glutamate decarboxylase (GADA), tyrosin phosphatase IA-2 (IA-2A) and insulin (IAA) antibodies was performed in serum samples obtained before and at 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10 and 13 months after the beginning of IFN-α treatment. Results Complete HLA class II typing was consistent with homozygosity for the HLA DRB *03011, DQA1 *0501, DQB1 *0201 haplotype. All autoantibodies were undetectable prior to IFN-α therapy and remained undetectable up to 6 months of treatment; at 8.5 months, at the time of diabetes onset, ICA were detectable at low titre while GADA were present at high titre. Both ICA and GADA persisted at high levels in subsequent samples. IA-2A remained undetectable in all serum samples, while IAA appeared only after treatment with exogenous insulin. Discussion This appears to be a case of autoimmune Type 1 diabetes induced by IFN-α treatment and developing on a predisposed genetic background with an unusually rapid development of the autoimmune process as reflected by the absence of detectable autoantibodies up to 2.5 months prior to disease onset. In this example of fulminant Type 1 diabetes a pathogenic process unbalanced towards a Th1-mediated autoimmune response is hypothesized. Diabet. Med. 18, 329–332 (2001). [ABSTRACT FROM AUTHOR]

In human cells the length of telomeres depends on telomerase activity. This activity and the expression of the catalytic subunit of human telomerase reverse transcriptase (hTERT) is strongly up-regulated in most human cancers. hTERT expression is regulated by different transcription factors, such as c-Myc, Mad1 and Sp1. In this study, we demonstrated that 15d-PG J2 and rosiglitazone (an endogenous and synthetic peroxisome proliferators activated receptor gamma (PPARgamma) ligand, respectively) inhibited hTERT expression and telomerase activity in CaCo-2 colon cancer cells. Moreover, both ligands inhibited c-Myc protein expression and its E-box DNA binding activity. Additionally, Mad1 protein expression and its E-box DNA binding activity were strongly increased by 15d-PG J2 and, to a lesser extent, by rosiglitazone. Sp1 transcription factor expression and its GC-box DNA binding activity were not affected by both PPARgamma ligands. Results obtained by transient transfection of CaCo-2 cells with pmaxFP-Green-PRL plasmid constructs containing the functional hTERT core promoter (including one E-box and five GC-boxes) and its E-box deleted sequences, cloned upstream of the green fluorescent protein reporter gene, demonstrated that 15d-PG J2, and with minor effectiveness, rosiglitazone, strongly reduced hTERT core promoter activity. E-boxes for Myc/Mad/Max binding showed a higher activity than GC-boxes for Sp1. By using GW9662, an antagonist of PPARgamma, we demonstrated that the effects of 15d-PG J2 are completely PPARgamma independent, whereas the effects of rosiglitazone on hTERT expression seem to be partially PPARgamma independent. The regulation of hTERT expression by 15d-PG J2 and rosiglitazone, through the modulation of the Myc/Max/Mad1 network, may represent a new mechanism of action of these substances in inhibiting cell proliferation.