ABSTRACT
Improving treatment of advanced melanoma may require the development of effective strategies to overcome resistance to different anti-tumor agents and to counteract relevant pro-tumoral mechanisms in the microenvironment. Here we provide preclinical evidence that these goals can be achieved in most melanomas, by co-targeting of oncogenic and death receptor pathways, and independently of their BRAF, NRAS, p53 and PTEN status. In 49 melanoma cell lines, we found independent susceptibility profiles for response to the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor BEZ235 and the death receptor ligand TRAIL, supporting the rationale for their association. Drug interaction analysis indicated that a strong synergistic anti-tumor activity could be achieved by the three agents and the AZD6244-TRAIL association on 20/21 melanomas, including cell lines resistant to the inhibitors or to TRAIL. Mechanistically, synergy was explained by enhanced induction of caspase-dependent apoptosis, mitochondrial depolarization and modulation of key regulators of extrinsic and intrinsic cell death pathways, including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members. Moreover, silencing experiments confirmed the central role of Apollon downmodulation in promoting the apoptotic response of melanoma cells to the combinatorial treatments. In SCID mice, the AZD6244-TRAIL association induced significant growth inhibition of a tumor resistant to TRAIL and poorly responsive to AZD6244, with no detectable adverse events on body weight and tissue histology. Reduction in tumor volume was associated not only with promotion of tumor apoptosis but also with suppression of the pro-angiogenic molecules HIF1α, VEGFα, IL-8 and TGFß1 and with inhibition of tumor angiogenesis. These results suggest that synergistic co-targeting of oncogenic and death receptor pathways can not only overcome melanoma resistance to different anti-tumor agents in vitro but can also promote pro-apoptotic effects and inhibition of tumor angiogenesis in vivo.
Subject(s)
Antineoplastic Agents/administration & dosage , Melanoma/drug therapy , Receptors, Death Domain/metabolism , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Benzimidazoles/administration & dosage , Cell Line, Tumor , Drug Resistance, Neoplasm , Drug Synergism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Melanoma/genetics , Melanoma/metabolism , Melanoma/physiopathology , Mice , Mice, SCID , Neovascularization, Pathologic , Receptors, Death Domain/genetics , TNF-Related Apoptosis-Inducing Ligand/administration & dosageABSTRACT
The aim of this study was to verify the association between the epidermal growth factor (EGF) +61 G/A polymorphism and the susceptibility to endometriosis using a case-control design study. The control group included fertile women without endometriosis and the case group included endometriosis patients. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to genotype the EGF +61 G/A polymorphism. Initially, a total of 184 individuals were analyzed. After matching by ethnicity, the control group was composed of 57 individuals, while the endometriosis group was composed of 57 patients. No statistically significant associations were observed between EGF +61 variants and the risk of endometriosis development (P>0.05). This is the first study correlating the EFG +61 G/A polymorphism and endometriosis in women from Brazil, and demonstrates that EFG +61 G/A is not associated with endometriosis susceptibility in Brazilian women.
Subject(s)
Endometriosis/genetics , Epidermal Growth Factor/genetics , Polymorphism, Genetic , Adult , Alleles , Brazil , Case-Control Studies , Endometriosis/pathology , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Risk FactorsABSTRACT
BACKGROUND: The present study assessed the effects of low-dose acarbose on obese patients with polycystic ovarian syndrome (PCOS). METHODS: A double-blind placebo-controlled study was conducted on 30 obese hyperinsulinaemic women with PCOS treated with 150 mg/day acarbose or placebo for 6 months. The women were evaluated for hirsutism, menstrual regularity, body mass index (BMI), insulin resistance and glucose tolerance, sex hormone-binding globulin (SHBG), LH, FSH, testosterone and androstenedione, and side-effects. RESULTS: The patients in the acarbose group showed a reduction in BMI (35.87 +/- 2.60 versus 33.10 +/- 2.94 kg/m(2)) and in the Ferriman-Gallwey index (8.85 +/- 2.31 versus 8 +/- 1.82), and an increased chance of menstrual regularity (rate = 2.67). SHBG concentration increased (21.01 +/- 7.9 versus 23.85 +/- 7.77 nmol/l) and the free androgen index was reduced (14.81 +/- 9.06 versus 11.48 +/- 6.18). None of these parameters were modified in the placebo group. Mild side-effects occurred in 84% of the patients in the acarbose group and disappeared after the first 3 months. CONCLUSION: A low dose of acarbose administered to obese patients with PCOS promotes a reduction in free androgen index and BMI and an increase in SHBG, with improvement of hirsutism and of the menstrual pattern, and is well tolerated by patients.
