Mcl-1 Antisense Therapy Chemosensitizes Human Melanoma in a SCID Mouse Xenotransplantation Model

It is well established that high expression of the antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL can significantly contribute to chemoresistance in a number of human malignancies. Much less is known about the role the more recently described Bcl-2 family member Mcl-1 might play in tumor biology and resistance to chemotherapy. Using an antisense strategy, we here address this issue in melanoma, a paradigm of a treatment-resistant malignancy. After in vitro proof of principle supporting an antisense mechanism of action with specific reduction of Mcl-1 protein as a consequence of nuclear uptake of the Mcl-1 antisense oligonucleotides employed, antisense and universal control oligonucleotides were administered systemically in combination with dacarbazine in a human melanoma SCID mouse xenotransplantation model. Dacarbazine, available now for more than three decades, still remains the most active single agent for treatment of advanced melanoma. Mcl-1 antisense oligonucleotides specifically reduced target protein expression as well as the apoptotic threshold of melanoma xenotransplants. Combined Mcl-1 antisense oligonucleotide plus dacarbazine treatment resulted in enhanced tumor cell apoptosis and led to a significantly reduced mean tumor weight (mean 0.16 g, 95% confidence interval 0.08–0.26) compared to the tumor weight in universal control oligonucleotide plus dacarbazine treated animals (mean 0.35 g, 95% confidence interval 0.2–0.44) or saline plus dacarbazine treated animals (mean 0.39 g, 95% confidence interval 0.25–0.53). We thus show that Mcl-1 is an important factor contributing to the chemoresistance of human melanoma in vivo. Antisense therapy against the Mcl-1 gene product, possibly in combination with antisense strategies targeting other antiapoptotic Bcl-2 family members, appears to be a rational and promising approach to help overcome treatment resistance of malignant melanoma

Archives of Gynecology and Obstetrics / Maternal and neonatal omentin-1 levels in gestational diabetes

Purpose To evaluate the effect of gestational diabetes on omentin-1 in maternal and cord plasma. As a potent mediator of insulin resistance, Omentin-1, an adipokine derived from human adipose and placental tissue, may be an important player in the pathophysiology of gestational diabetes. Methods This was a prospective casecontrol study. The study included 96 women with gestational diabetes and 96 pregnant women without. Omentin-1 was measured at the time of the oral glucose tolerance test, at 32 weeks in maternal plasma and right after delivery in umbilical cord blood by ELISA assay. Results Over a period of 2 years, 200 patients were enrolled. Omentin-1 levels did not significantly differ between both groups throughout the pregnancy: omentin-1 levels were 157 83 ng/ml in women with gestational diabetes and 158 93 ng/ml in women without gestational diabetes (p = 0.94) at time of the oral glucose tolerance test and 118 77 ng/ml in women with diabetes and 150 89 ng/ml in women without (p = 0.12) at 32 weeks, respectively. Both groups showed a decrease in omentin-1 levels throughout pregnancy, with a more pronounced decrease in diabetic women (13 53 versus 4 48 ng/ml; p = 0.5). Neonatal omentin-1 levels were significantly lower in offspring of diabetic mothers: 106 61 versus 134 45 ng/ml (p = 0.03). Conclusions There was no significant difference in omentin-1 levels between healthy and diabetic mothers throughout the pregnancy. However, we found significantly lower omentin-1 levels in offspring of diabetic mothers. This may indicate a risk for the development of insulin resistance in later life.(VLID)357507

Involvement of nitric oxide in angiogenic activities of vascular endothelial growth factor isoforms

Wydział Biotechnologi