XIAP-targeted prostate cancer therapy

A treatment for prostate cancer using cyclin-dependent kinase inhibitors is provided. The effects of cyclin-dependent kinase inhibitors on the survival of prostate cancer cells was examined. Roscovitine, R-roscovitine, and CGP74514A were shown to induce the apoptosis of LNCaP and LNCaP-Rf cells, both of which express wild-type p53. The cyclin-dependent kinase inhibitors of the present invention induce the mitochondria-mediated apoptosis of prostate cancer cells by a dual mechanism: p53 accumulation and XIAP depletion

Roscovitine inhibits differentiation and invasion in a three-dimensional skin reconstruction model of metastatic melanoma

The aim of this study was to investigate the therapeutic potential of a cyclin-dependent kinase inhibitor, roscovitine, in cultured melanoma cells and a three-dimensional skin reconstruction model of metastatic melanoma. The modulatory effects of roscovitine on the growth and survival of normal melanocytes and cultured melanoma cell lines were tested. Additionally, we investigated the potential of roscovitine to regulate the growth and differentiation of a metastatic melanoma cell line (A375) in a three-dimensional skin reconstruction culture consisting of A375 cells admixed with normal human keratinocytes embedded within a collagen-constricted fibroblast matrix. We show that roscovitine is able to induce apoptosis in the melanoma cell lines A375, 888, and 624 but not in normal human cultured epithelial melanocytes. The degree of apoptosis within these cell lines correlated with the accumulation of p53 protein and concomitant reduction of X-linked inhibitor of apoptosis protein, with no change in the proteins Bcl-2 and survivin. We also found that roscovitine inhibited the growth and differentiation of A375 melanoma cells within the dermal layer of the skin. The results of this study show that roscovitine has the potential to inhibit the differentiation and invasion of metastatic melanoma and may be useful as a therapy for the treatment of patients with metastatic melanoma

Ras p27 mouse models and uses thereof

The subject invention pertains to a transgenic animal model for tumorigenesis having a genome comprising a ras transgene and which is heterozygous or homozygous for a null p27 gene, and methods of using such animal to screen compounds or evaluate treatments for oncogenic and antitumor activity. The subject invention further concerns a transgenic mouse comprising a ras transgene and which has a genome that is wild-type p27+/+, and wherein the mouse has an FVB/N and C57BL/6X 129 genetic background; and methods of using such transgenic mice to screen compounds or evaluate treatments for oncogenic or antitumor activity. Advantageously, the female animals of the subject invention are fertile and capable of nursing their young. The subject invention also pertains to in vitro systems including isolated cells or tissues of animal models for tumorigenesis, which can be used to screen compounds and treatments for oncogenic and antitumor activity

Protein expression of MMP2, TIMP2 in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patient survival.

5009 Background/Aims: Matrix metalloproteinase-2 (MMP-2) is involved in the processes of tumor invasion and metastasis. However, studies on MMP-2 and tissue inhibitor of MMP-2 (TIMP-2) in hepatocellular carcinoma (HCC) are rare, and there are no studies on the correlations with these expressions and HCC patient’s suvival. Methods : We immunohistochemically examined the expression of these proteins and the relationships between these expressions and histological grade, clinicopathological parameters and patient’s survival in 106 patients with HCC. We also examined gelatin zymography and western blotting, using 12 fresh samples of HCC. Results : MMP-2 and TIMP-2 immunoreactivities were presented in HCC cells as well as in non-HCC cells. MMP-2 expression significantly correlated with TIMP-2 expression, and these expressions were stronger in non-tumorous lesions than in tumor lesions. These immunohistochemical results were nearly consistent with the results of western blotting. MMP-2 expression significantly correlated with HCC grade. Though there were no relations between the MMP-2 or TIMP-2 expression and several clinicopathological parameters, overexpressions of MMP-2 and TIMP-2 were associated with poor prognosis of HCC’s patients. Moreovre, TIMP-2 expression was identified as the best predictive factor for determining the prognosis in patients with HCC. Conclusion : MMP-2 and TIMP-2 are involved in HCC progression, and their overexpression is associated with poor prognosis