Increases in nuclear calcium concentration generate specific biological outcomes that differ from those resulting from increased cytoplasmic calcium. Nuclear calcium effects on tumor cell proliferation are widely appreciated; nevertheless, its involvement in other steps of tumor progression is not well understood. Therefore, we evaluated whether nuclear calcium is essential in other additional stages of tumor progression, including key steps associated with the formation of the primary tumor or with the metastatic cascade. We found that nuclear calcium buffering impaired 4T1 triple negative breast cancer growth not just by decreasing tumor cell proliferation, but also by enhancing tumor necrosis. Moreover, nuclear calcium regulates tumor angiogenesis through a mechanism that involves the upregulation of the anti-angiogenic C-X-C motif chemokine 10 (CXCL10-IP10). In addition, nuclear calcium buffering regulates breast tumor cell motility, culminating in less cell invasion, likely due to enhanced vinculin expression, a focal adhesion structural protein. Together, our results show that nuclear calcium is essential for triple breast cancer angiogenesis and cell migration and can be considered as a promising strategic target for triple negative breast cancer therapy.

Abstract:The in vitro antifungal activity of nine dirutheniumpentadithiocarbamate complexes C1-C9 was investigated and assessed for its activity against four different fungal species with clinical interest and related to invasive fungal infections (IFIs), such as Candida spp. influence from steric and lipophilic parameters in the antifungal activity can be noticed. Cytotoxicity assays (IC 50 ) showed that the complexes are not as toxic (IC 50 values are much higher-30 to 200 fold-than MIC values). These ruthenium complexes are very promising lead compounds for novel antifungal drug development, especially in IFIs, one of most harmful emerging infection diseases (EIDs).

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These results can explain the gastroprotective activity of P1G10 and serve a basis for further studies of this active principle.

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The proteolytic fraction (P1G10) from Vasconcellea cundinamarcensis, displays gastric protective and healing activities in different skin lesions in mice and human. In an excisional model, this fraction accelerates resolution of lesions and modulates inflammatory mediators. Based on these data, we assessed its anti-inflammatory activity in murine colitis model, induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) adopted by its physiopathological similarity with human colitis. Twenty four hours after colitis induction followed by three days of treatment, P1G10 at 0.3 and 3.0 mg/Kg induced 30% increase in body weight (p < 0.0001) and ~80% reduction in colon macroscopic damage score (p < 0.05) compared to the untreated TNBS-induced colitis group. Histological analyses showed that 0.3 mg/Kg P1G10 reduced the inflammatory profile and tissue damage (47%, p < 0.05) when it was proteolytically active. Compared to TNBS group, 0.3 mg/Kg P1G10 reduced MPO activity (80%, p < 0.01), MCP-1 (47%, p < 0.05) and TNF-α (50%, no significant) and increased IL-10 (330%, p < 0.001) levels in the supernatant of colonic tissue homogenate. P1G10 treatment also reduced COX-2 expression (60%, p < 0.05) and metalloprotease-2 activity (39%, p < 0.05) while increased globet cell density (140%, p < 0.01), that contributes to mucus layer protection in colonic tissue. Taken together, these findings suggest that low doses of active P1G10 promotes lesion resolution, at least in part by its anti-inflammatory activity, in TNBS-colitis model.

The aim of this study was to evaluate the therapy effect of thalidomide in the 4T1 murine mammary carcinoma. 4T1 cell suspension was injected into the posterior left flank of all animals to obtain solid tumors. Five days after inoculation, the treatment group was orally administered 150 mg/kg of thalidomide for seven days. Tumors were measured every 48 hours until the end of treatment. Whole blood was collected for hematology analysis. Our results suggest that thalidomide therapy increase the number of circulating leukocytes in the 4T1 murine mammary carcinoma, and this response is accompanied by a decrease in tumor growth.

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