RESUMO
Ketoconazole, an antifungal agent, has been used to inhibit hormone synthesis in types of prostate and breast cancer. Immunomodulatory proteins of Ganoderma microsporum (GMI) inhibit the tumor necrosis factor-α- and epidermal growth factor-induced metastatic ability of lung cancer cells. Cutaneous malignant melanoma is a highly invasive and metastatic skin cancer. However, to the best of our knowledge, there is limited understanding regarding the effects of ketoconazole and GMI on melanoma. The current study aimed to investigate the inhibitory effects of GMI combined with ketoconazole on melanoma survival and metastasis. The effects of GMI combined with ketoconazole on the viability, migration and protein expression of melanoma cells were determined by MTT assay, Boyden chamber assay and western blot analysis, respectively. The expression of monocyte chemoattractant protein-1 (MCP-1) was investigated by enzyme-linked immunoabsorbent assay. The present results indicate that ketoconazole enhances the GMI-induced decrease in proliferation and migration of A375.S2 melanoma cells in a concentration-dependent manner. Ketoconazole was identified to reduce the level of GMI-induced phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK)-α and autophagy; however, ketoconazole did not affect p-AMPK-ß levels in A375.S2 cells. In addition, ketoconazole and dorsomorphin dihydrochloride, an AMPK inhibitor, were revealed to reduce MCP-1 secretion in A375.S2 cells. In summary, the present study revealed that ketoconazole enhances GMI-inhibited proliferation and migration of A375.S2 melanoma cancer cells, and inhibits the secretion of MCP-1.
RESUMO
OBJECTIVE: To investigate the association between insulin secretion and plasma glucose levels, and the potential effect of plasma glucose concentration on insulin secretion stimulated by glucose in patients with type 2 diabetes. METHODS: A total of 124 patients with type 2 diabetes were enrolled to undergo 75 g oral glucose tolerance test (OGTT) and insulin releasing test (IRT), 24 h after discontinuation of oral hypoglycemic agent or insulin injection. The plasma levels of glucose and insulin, effects of fasting and postprandial plasma levels of glucose and insulin, the time of maximal glucose value in OGTT, the ratio of maximal to basal glucose levels (M/Bg) were determined to assess their effects on the basal and stimulated insulin secretion. RESULTS: Correlation test demonstrated that there was a significant inverse correlation between fasting blood glucose and the insulin levels measured at all the time points of IRT. The plasma glucose levels during OGTT were inversely correlated with plasma insulin levels during IRT (instead of basal insulin level), and the relations were especially significant of all the glucose levels at 5 time points during OGTT with the insulin levels at 1, 2 h, the maximal insulin level (Imax) and the maximal-to-basal insulin level ratio (M/Bi). The ratio of maximal glucose to fasting glucose was positively correlated with the insulin levels at the 5 time points and Imax. The Imax and M/Bi of the patients whose fasting glucose exceeded 11.1 mmol/L were roughly one third of those whose base blood glucose was less than 11.1 mmol/L (P<0.01); when the 2-hour glucose exceeded 16.7 mmo/L, a reduction of more than half occurred in Imax and M/Bi (P<0.01-0.05), which doubled when M/Bg was larger than 2. CONCLUSION: Hyperglycemia (fasting or postprandial glucose) of type-2 diabetic patients has considerably destructive effect on dynamic insulin secretion.