cyclin-d1 and phosphorylethanolamine

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and represents the third most common urological malignancy. Despite the advent of targeted therapies for RCC and the improvement of the lifespan of patients, its cost-effectiveness restricted the therapeutic efficacy. In a recent report, we showed that synthetic phosphoethanolamine (Pho-s) has a broad antitumor activity on a variety of tumor cells and showed potent inhibitor effects on tumor progress in vivo.. We show that murine renal carcinoma (Renca) is more sensitive to Pho-s when compared to normal immortalized rat proximal tubule cells (IRPTC) and human umbilical vein endothelial cells (HUVEC). In vitro anti-angiogenic activity assays show that Pho-s inhibits endothelial cell proliferation, migration and tube formation. In addition, Pho-s has anti-proliferative effects on HUVEC by inducing a cell cycle arrest at the G2/M phase. It causes a decrease in cyclin D1 mRNA, VEGFR1 gene transcription and VEGFR1 receptor expression. Pho-s also induces nuclear fragmentation and affects the organization of the cytoskeleton through the disruption of actin filaments. Additionally, Pho-s induces apoptosis through the mitochondrial pathway. The putative therapeutic potential of Pho-s was validated in a renal carcinoma model, on which our remarkable in vivo results show that Pho-s potentially inhibits lung metastasis in nude mice, with a superior efficacy when compared to Sunitinib.. Taken together, our findings provide evidence that Pho-s is a compound that potently inhibits lung metastasis, suggesting that it is a promising novel candidate drug for future developments.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin D1; Cytoskeleton; Ethanolamines; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Indoles; Kidney Tubules, Proximal; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitochondria; Neoplasm Metastasis; Neovascularization, Pathologic; Oxidation-Reduction; Pyrroles; Rats; Sunitinib; Transcription, Genetic; Vascular Endothelial Growth Factor Receptor-1; Wound Healing

Phosphoethanolamine (Pho-s) is a compound involved in phospholipid turnover, acting as a substrate for many phospholipids of the cell membranes. In a recent study, we showed that Pho-s has antitumor effect in the several tumor cells. In this study we evaluated the antitumor activity of synthetic Pho-s on MCF-7 breast cancer cells. Here we demonstrate that Pho-s is cytotoxic to MCF-7 cells in a dose-dependent manner, while it is cytotoxic to MCF10 only at higher concentrations. In addition, Pho-s induces a disruption in mitochondrial membrane potential (Δψm). Furthermore, Pho-s induces mitochondria aggregates in the cytoplasm and DNA fragmentation of MCF-7 cells visualized by confocal microscopy. In agreement with the reduction on Δψm, we showed that Pho-s induces apoptosis followed by an increase in cytochrome c expression and capase-3-like activity in MCF-7 cells. Our results demonstrate that Pho-s induces a cell cycle arrest in the G1 phase through an inhibition of cyclin D1 and stimulates p53. An additional highlight of this study is the finding that Pho-s inhibits Bcl-2, inducing apoptosis through the mitochondrial pathway. Taken together, these results show that Pho-s is a promising compound in the fight against cancer.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspase 3; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cyclin D1; Cytochromes c; Cytoplasm; DNA Fragmentation; Ethanolamines; Female; G1 Phase; Humans; MCF-7 Cells; Membrane Potential, Mitochondrial; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Suppressor Protein p53