A Small Molecule SMAC Mimic LBW242 Potentiates TRAIL- and Anticancer Drug-Mediated Cell Death of Ovarian Cancer Cells

BACKGROUND: Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays. PRINCIPAL FINDINGS: LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis. CONCLUSION: LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer

The low-molecular-weight heparin, nadroparin, inhibits tumour angiogenesis in a rodent dorsal skinfold chamber model

BACKGROUND: Recently, low-molecular-weight heparins (LMWHs) were found to confer a survival advantage in cancer patients. The mechanism underlying this observation is unclear, but may involve inhibition of tumour angiogenesis. We aimed to examine the effects of nadroparin on tumour angiogenesis using a dorsal skinfold window chamber model in the Syrian hamster. METHODS: AMel-3 and HAP-T1 tumours were grown in donor animals and fragments implanted in the window chambers. Animals (N=46) were treated with 200 IU of nadroparin or saline for 10 days. Repeated intravital fluorescence microscopy was performed to calculate functional microcirculatory parameters: number (N) and length (L) of microvessels, vascular area fraction (AF), and red blood cell velocity (V). Microvessel density (MVD), fractal dimension, and pericyte coverage were assessed histologically. RESULTS: Active angiogenesis was observed in control animals, resulting in a significant increase in N, L, and AF. In nadroparin-treated animals, however, N and L did not increase whereas AF decreased significantly. Both groups showed an initial increase in V, but nadroparin treatment resulted in an earlier decrease in red blood cell velocity over time. Compared with control animals, nadroparin-treated animals showed a significantly lower MVD and fractal dimension but significantly higher pericyte coverage index (PCI). CONCLUSIONS: Taken together, these results suggest that the LMWH nadroparin inhibits tumour angiogenesis and results in microvessel normalisation