The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways.

Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for potential anticancer activity so far. We found that deslanoside effectively inhibited colony formation in vitro and tumor growth in nude mice of PCa cell lines 22Rv1, PC-3, and DU 145. Such an anticancer activity was mediated by both the cell cycle arrest at G2/M and the induction of apoptosis, as demonstrated by different functional assays and the expression status of regulatory proteins of cell cycle and apoptosis in cultured cells. Moreover, deslanoside suppressed the invasion and migration of PCa cell lines. Genome-wide expression profiling and bioinformatic analyses revealed that 130 genes were either upregulated or downregulated by deslanoside in both 22Rv1 and PC-3 cell lines. These genes enriched multiple cellular processes, such as response to steroid hormones, regulation of lipid metabolism, epithelial cell proliferation and its regulation, and negative regulation of cell migration. They also enriched multiple signaling pathways, such as necroptosis, MAPK, NOD-like receptor, and focal adhesion. Survival analyses of the 130 genes in the TCGA PCa database revealed that 10 of the deslanoside-downregulated genes (ITG2B, CNIH2, FBF1, PABPC1L, MMP11, DUSP9, TMEM121, SOX18, CMPK2, and MAMDC4) inversely correlated, while one deslanoside-upregulated gene (RASD1) positively correlated, with disease-free survival in PCa patients. In addition, one deslanoside-downregulated gene (ENG) inversely correlated, while three upregulated genes (JUN, MXD1, and AQP3) positively correlated with overall survival in PCa patients. Some of the 15 genes have not been implicated in cancer before. These findings provide another candidate for repurposing cardiac glycosides for anticancer drugs. They also suggest that a diverse range of molecular events underlie deslanoside's anticancer activity in PCa cells.

[Effects of cardiac support on delayed resuscitation in extensively burned patients with shock].

Objective: To explore the effects of cardiac support on delayed resuscitation in extensively burned patients with shock. Methods: Clinical data of 62 extensively burned patients with shock on admission, admitted to the 159th Hospital of PLA (hereinafter referred to as our hospital) from January 2012 to January 2017, were retrospectively analyzed. They were divided into cardiac support group (n=35) and control group (n=27) according to the use of deslanoside and ulinastatin. All patients were treated with routine fluid resuscitation based on the formula of the Third Military Medical University till post injury hour (PIH) 48. Patients in cardiac support group were given slow intravenous injection of deslanoside which was added in 20 mL 100 g/L glucose injection with first dose of 0.4 to 0.6 mg, 0.2 to 0.4 mg per 6 to 8 h, no more than 1.6 mg daily, and slow intravenous injection of 1×10(5)U ulinastatin which was added in 100 mL 50 g/L glucose injection, once per 12 h. Other treatments of patients in the two groups followed the same conventional procedures of our hospital. The following data of the two groups of patients were collected. (1) The data of urine volume per hour within PIH 48, heart rate, mean arterial pressure (MAP), central venous pressure (CVP), blood lactic acid, base excess, hematocrit, and albumin at PIH 48 were recorded. (2) The input volumes of electrolyte, colloid within the first and second 24 hours post burn and the total fluid input volumes within PIH 48 were recorded. (3) The data of creatine kinase, creatine kinase isoenzyme-MB, lactate dehydrogenase, total bile acid, alanine aminotransferase, aspartate aminotransferase, ß(2)-microglobulin, urea nitrogen, and creatinine at PIH 48 were recorded. (4) The complications including cardiac failure, pulmonary edema, pleural effusion, seroperitoneum, renal failure, sepsis, and death were also recorded. Data were processed with independent sample ttest, Fisher's exact test, Pearson chi-square test, or continuous correction chi-square test. Results: (1) There were no statistically significant differences in urine volume within PIH 48, heart rate, MAP, CVP, hematocrit, or albumin at PIH 48 between the patients of two groups (t=0.150, 0.488, 0.805, 0.562, 1.742, 0.696, P>0.05). While the levels of blood lactic acid and base excess were respectively (4.2±2.2) and (-4.3±2.0) mmol/L in patients of cardiac support group, which were significantly better than (5.9±1.7) and (-6.0±3.1) mmol/L in patients of control group (t=3.249, 2.480, P<0.05 or P<0.01). (2) There was no statistically significant difference in input volume of colloid within the first 24 hours post burn between the patients of two groups (t=0.642, P>0.05). The input volume of electrolyte within the first 24 hours post burn, the input volumes of electrolyte and colloid within the second 24 hours post burn, and the total fluid input volume within PIH 48 of patients in cardiac support group were significantly less than those in control group (t=2.703, 4.223, 3.437, 2.515, P<0.05 or P<0.01). (3) The levels of creatine kinase, creatine kinase isoenzyme-MB, lactate dehydrogenase, total bile acid, alanine aminotransferase, aspartate aminotransferase, ß(2)-microglobulin, urea nitrogen, and creatinine of patients in cardiac support group at PIH 48 were significantly lower than those in control group (t=3.066, 3.963, 3.225, 2.943, 2.431, 3.084, 4.052, 2.915, 3.353, P<0.05 or P<0.01). (4) The occurrences of pleural effusion and seroperitoneum and mortality of patients in cardiac support group were significantly lower than those in control group (χ(2)=5.514, 6.984, 4.798, P<0.05 or P<0.01). There were no statistically significant differences in cardiac failure, pulmonary edema, renal failure, and sepsis between the patients of two groups [χ(2)=1.314 (sepsis), P>0.05]. Conclusions: The cardiotonic and cardiac protection treatments in delayed resuscitation of extensively burned patients with shock contribute to improving the cellular anonic metabolism, reducing the volume of fluid resuscitation, and mitigating the ischemic and hypoxic damage to organs, so as to lay foundation for decreasing further complication incidences and mortality.

Effects of cardiac support on delayed resuscitation in extensively burned patients with shock / 中华烧伤杂志

Objective@#To explore the effects of cardiac support on delayed resuscitation in extensively burned patients with shock.@*Methods@#Clinical data of 62 extensively burned patients with shock on admission, admitted to the 159th Hospital of PLA (hereinafter referred to as our hospital) from January 2012 to January 2017, were retrospectively analyzed. They were divided into cardiac support group (n=35) and control group (n=27) according to the use of deslanoside and ulinastatin. All patients were treated with routine fluid resuscitation based on the formula of the Third Military Medical University till post injury hour (PIH) 48. Patients in cardiac support group were given slow intravenous injection of deslanoside which was added in 20 mL 100 g/L glucose injection with first dose of 0.4 to 0.6 mg, 0.2 to 0.4 mg per 6 to 8 h, no more than 1.6 mg daily, and slow intravenous injection of 1×105U ulinastatin which was added in 100 mL 50 g/L glucose injection, once per 12 h. Other treatments of patients in the two groups followed the same conventional procedures of our hospital. The following data of the two groups of patients were collected. (1) The data of urine volume per hour within PIH 48, heart rate, mean arterial pressure (MAP), central venous pressure (CVP), blood lactic acid, base excess, hematocrit, and albumin at PIH 48 were recorded. (2) The input volumes of electrolyte, colloid within the first and second 24 hours post burn and the total fluid input volumes within PIH 48 were recorded. (3) The data of creatine kinase, creatine kinase isoenzyme-MB, lactate dehydrogenase, total bile acid, alanine aminotransferase, aspartate aminotransferase, β2-microglobulin, urea nitrogen, and creatinine at PIH 48 were recorded. (4) The complications including cardiac failure, pulmonary edema, pleural effusion, seroperitoneum, renal failure, sepsis, and death were also recorded. Data were processed with independent sample ttest, Fisher′s exact test, Pearson chi-square test, or continuous correction chi-square test.@*Results@#(1) There were no statistically significant differences in urine volume within PIH 48, heart rate, MAP, CVP, hematocrit, or albumin at PIH 48 between the patients of two groups (t=0.150, 0.488, 0.805, 0.562, 1.742, 0.696, P>0.05). While the levels of blood lactic acid and base excess were respectively (4.2±2.2) and (-4.3±2.0) mmol/L in patients of cardiac support group, which were significantly better than (5.9±1.7) and (-6.0±3.1) mmol/L in patients of control group (t=3.249, 2.480, P<0.05 or P<0.01). (2) There was no statistically significant difference in input volume of colloid within the first 24 hours post burn between the patients of two groups (t=0.642, P>0.05). The input volume of electrolyte within the first 24 hours post burn, the input volumes of electrolyte and colloid within the second 24 hours post burn, and the total fluid input volume within PIH 48 of patients in cardiac support group were significantly less than those in control group (t=2.703, 4.223, 3.437, 2.515, P<0.05 or P<0.01). (3) The levels of creatine kinase, creatine kinase isoenzyme-MB, lactate dehydrogenase, total bile acid, alanine aminotransferase, aspartate aminotransferase, β2-microglobulin, urea nitrogen, and creatinine of patients in cardiac support group at PIH 48 were significantly lower than those in control group (t=3.066, 3.963, 3.225, 2.943, 2.431, 3.084, 4.052, 2.915, 3.353, P<0.05 or P<0.01). (4) The occurrences of pleural effusion and seroperitoneum and mortality of patients in cardiac support group were significantly lower than those in control group (χ2=5.514, 6.984, 4.798, P<0.05 or P<0.01). There were no statistically significant differences in cardiac failure, pulmonary edema, renal failure, and sepsis between the patients of two groups [χ2=1.314 (sepsis), P>0.05].@*Conclusions@#The cardiotonic and cardiac protection treatments in delayed resuscitation of extensively burned patients with shock contribute to improving the cellular anonic metabolism, reducing the volume of fluid resuscitation, and mitigating the ischemic and hypoxic damage to organs, so as to lay foundation for decreasing further complication incidences and mortality.

Characteristics of deslanoside-induced modulation on jejunal contractility.

AIM: To characterize the dual effects of deslanoside on the contractility of jejunal smooth muscle. METHODS: Eight pairs of different low and high contractile states of isolated jejunal smooth muscle fragment (JSMF) were established. Contractile amplitude of JSMF in different low and high contractile states was selected to determine the effects of deslanoside, and Western blotting analysis was performed to measure the effects of deslanoside on myosin phosphorylation of jejunal smooth muscle. RESULTS: Stimulatory effects on the contractility of JSMF were induced (45.3% ± 4.0% vs 87.0% ± 7.8%, P < 0.01) by deslanoside in 8 low contractile states, and inhibitory effects were induced (180.6% ± 17.8% vs 109.9% ± 10.8%, P < 0.01) on the contractility of JSMF in 8 high contractile states. The effect of deslanoside on the phosphorylation of myosin light chain of JSMF in low (78.1% ± 4.1% vs 96.0% ± 8.1%, P < 0.01) and high contractile state (139.2% ± 8.5% vs 105.5 ± 7.34, P < 0.01) was also bidirectional. Bidirectional regulation (BR) was abolished in the presence of tetrodotoxin. Deslanoside did not affect jejunal contractility pretreated with the Ca(2+) channel blocker verapamil or in a Ca(2+)-free assay condition. The stimulatory effect of deslanoside on JSMF in a low contractile state (low Ca(2+) induced) was abolished by atropine. The inhibitory effect of deslanoside on jejunal contractility in a high contractile state (high Ca(2+) induced) was blocked by phentolamine, propranolol and L-NG-nitro-arginine, respectively. CONCLUSION: Deslanoside-induced BR is Ca(2+) dependent and is related to cholinergic and adrenergic systems when JSMF is in low or high contractile states.