Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives

Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtained from the root of Sanguinaria canadensis, and from other poppy Fumaria species, with recognized anti-microbial, anti-oxidant and anti-inflammatory properties. Recently, increasing evidence that sanguinarine exibits anticancer potential through its capability of inducing apoptosis and/or antiproliferative effects on tumor cells, has been proved. Moreover, its antitumor seems to be due not only to its pro-apoptotic and inhibitory effects on tumor growth, but also to its antiangiogenic and anti-invasive properties. Although the precise mechanisms underlying the antitumor activity of this compound remain not fully understood, in this review we will focus on the most recent findings about the cellular and molecular pathways affected by sanguinarine, together with the rationale of its potential application in clinic. The complex of data currently available suggest the potential application of sanguinarine as an adjuvant in the therapy of cancer, but further pre-clinical studies are needed before such an antitumor strategy can be effectively translated in the clinical practice.     

Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome

AIM:To describe our patients affected with ectopic biliary tree gastrinoma and review the literature on this topic.METHODS:Between January 1992 and June 2012,28 patients affected by duodenopancreatic endocrine tumors in multiple endocrine neoplasia type 1(MEN1)syndrome underwent surgery at our institution.This retrospective review article analyzes our experience regarding seventeen of these patients subjected to duodenopancreatic surgery for Zollinger-Ellison syndrome(ZES).Surgical treatment consisted of duodenopancreatectomy(DP)or total pancreatectomy(TP).Regional lymphadenectomy was always performed.Any hepatic tumoral lesions found were removed during surgery.In MEN1 patients,removal of duodenal lesions can sometimes lead to persistence or recurrence of hypergastrinemia.One possible explanation for this unfavorable outcome could be unrecognized ectopic localization of gastrin-secreting tumors.This study described three cases among the seventeen patients who were found to have an ectopic gastrinoma located in the biliary tree.RESULTS:Seventeen MEN1 patients affected with ZES were analyzed.The mean age was 40 years.Fifteen patients underwent DP and two TP.On histopathological examination,duodeno pancreatic endocrine tumors were found in all 17 patients.Eighty-one gastrinomas were detected in the first three portions of the duodenum.Only one gastrinoma was found in the pancreas.The mean number of gastrinomas per patient was 5(range 1-16).Malignancy was established in 12 patients(70.5%)after lymph node,liver and omental metastases were found.Three patients exhibited biliary tree gastrinomas as well as duodenal gastrinoma(s).In two cases,the ectopic gastrinoma was removed at the same time as pancreatic surgery,while in the third case,the biliary tree gastrinoma was resected one year after DP because of recurrence of ZES.CONCLUSION:These findings suggest the importance of checking for the presence of ectopic gastrinomas in the biliary tree in MEN1 patients undergoing ZES surgery.     

Ascites,pleural, and pericardial effusions in acute pancreatitis

Ascites and pleural and pericardial effusions can be observed during acute pancreatitis. The aims of this study were to evaluate their incidence, natural history, and prognostic role in patients with acute pancreatitis. One hundred patients consecutively admitted with a diagnosis of acute pancreatitis were prospectively submitted to abdominal, pleural, and cardiac ultrasonography at admission and during follow-up. Ascites was found in 18 patients, pleural effusion in 20, and pericardial effusion in 17. Twenty-four patients of this series had severe pancreatitis; three of them died. All effusions disappeared spontaneously in patients who survived pancreatitis up to two months after dismissal. At multivariate analysis ascites and pleural effusion were demonstrated to be accurate independent predictors of severity. The respective odds ratios were 5.9 [95% confidence interval (CI), 1.5–23.0%) and 8.6 (95% CI, 2.3–32.5%). Furthermore the presence of pleural effusion, ascites, and pericardial effusion were associated with an increased incidence of pseudocyst during follow-up. Ascites and pleural and pericardial effusions are frequent during acute pancreatitis. Pleural effusion and ascites are accurate predictors of severity in these patients.     

Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease

Peripheral arterial disease (PAD) is a predictor of cardiovascular risk. However, it is unknown whether PAD severity influences inflammatory status and endothelial function, which play a major role in atherosclerosis. Accordingly, we measured brachial artery flow-mediated dilation (FMD), and plasma levels of several inflammatory markers in 15 control subjects, and 19 asymptomatic and 19 symptomatic PAD patients. Each symptomatic patient was matched to an asymptomatic patient for age, sex, risk factors, presence of cardiovascular disease, and pharmacological treatments. Asymptomatic patients had similar inflammatory profiles as controls, but lower median FMD (11.7% vs 8.5%, p < 0.01). Compared with asymptomatic patients, symptomatic patients had higher median C-reactive protein (1.5 mg/l vs 6.0 mg/l, p < 0.05) and interleukine-6 (1.5 pg/ml vs 3.5 pg/ml, p < 0.05), and lower FMD (8.5% vs 5.1%, p < 0.01). In the 38 PAD patients, the ankle/brachial pressure index correlated positively with FMD (p < 0.01), and negatively with C-reactive protein (p < 0.05), soluble intercellular adhesion molecule-1 (p < 0.05) and soluble vascular cell adhesion molecule-1 (p < 0.05). Thus, in PAD, endothelial function and inflammatory status are related to the severity of the circulatory impairment. This finding may contribute to the explanation of the increasingly poor prognosis with increased PAD severity.     

Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations.

AIMS: Retrospective studies have identified a mutation in the lamin A/C (LMNA) gene in patients selected on the basis of a phenotype characterized by dilated cardiomyopathy, atrioventricular conduction disturbances and sudden death. However, the features of cardiac abnormalities in patients with an initial diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) are poorly known. Aim of the present study was to investigate the spectrum of cardiac disease in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene. METHODS AND RESULTS: Ten consecutive patients with EDMD and a LMNA gene mutation were evaluated with structured medical interview, physical examination, ECG, echocardiogram and 24-h Holter monitoring. Electrophysiological testing and cardiac catheterization were performed if a class 1 or 2 American Heart Association guidelines indication was present. Cardiac disease was found in eight of 10 patients and consisted in the variable combination of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated cardiomyopathy, non-dilated cardiomyopathy, restrictive cardiomyopathy and sudden death despite pacemaker implant. CONCLUSIONS: Cardiac disease is common in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene and consists of arrhythmias, disorders of atrioventricular conduction, cardiomyopathies and sudden death despite pacemaker implant.     

The effect of carbon tetrachloride and ultraviolet radiation on dolichol levels in liver cells isolated from 3- and 24-month-old male Sprague-Dawley rats

Dolichol (D) is a long-chain polyprenoid broadly distributed in the cell membranes, possibly endowed with a free-radical scavenging activity, whose concentration in tissues increases with increasing age. No enzyme pathway for D degradation has been discovered. In order to test the hypothesis that D might undergo a non-enzymatic free-radical mediated decomposition the effects of a xenobiotic agent (carbon tetrachloride, CCl(4)) and ultraviolet-B (UV-B) radiation on D levels were studied in liver cells isolated from male ad libitum fed Sprague-Dawley rats aged 3 or 24 months. Liver cells (90 mg/ml) were incubated in sealed flasks (6 ml cell suspension each) for 0, 5, 10 and 20 min after the addition of 25, 50 or 200 microl CCl(4) in the central well. 50 ml of a 6 mg/ml liver cell suspension were poured in a 120 cm(2) Petri dish and the sediment liver cell monolayer was exposed to UVB radiation for 0, 5, 10, 20 and 40 min. At the given time, cells were taken and D was extracted and assayed by the HPLC procedure. D levels were remarkably higher in older than in younger cells as expected ( P < 0.001). Treatment with CCl(4) and UVB caused a highly significant decrease in D ( P < 0.001) whose percentage was larger in younger than in older cells. The conclusions are that free-radicals generated either by chemical or by physical agents cause a very rapid depletion of D in liver cells, and that the effect of the free radical attack on D decomposition may be lower percentage wise in older than in younger cells, which might account at least in part for the accumulation of D in older tissues.