Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

Effects of probiotic bacteria (VSL#3) on the polyamine biosynthesis and cell proliferation of normal colonic mucosa of rats

Abstract. Background: Probiotics seem to possess tumour inhibitory properties, but few studies have investigated their actions on the cell proliferation of normal colonic mucosa. The effects of a probiotic mixture (VSL#3) on polyamine biosynthesis, Ki-67 levels and apoptosis in the normal colon of rats were studied. Materials and Methods: For a 4-week period, 20 rats were fed a VSL#3 solution and 20 rats a saline solution. Samples from the colonic mucosa were collected at the end of treatment. Polyamines were detected by HPLC, ornithine decarboxylase activity by a radiometric technique, and apoptosis and Ki-67 by histochemical and immunohistochemical methods. Results: VSL#3 caused a significant decrease in colonic polyamine levels, ornithine decarboxylase activity and Ki-67 compared to controls. A significant increase in the apoptotic index was also observed. Conclusion: Probiotics could also reduce proliferation rates in a condition not affected by hyperproliferative or neoplastic growth, when the normal control mechanisms are still completely effective

Insulin plasma levels in pregnant patients with impaired glucose tolerance: relationship with pregnancy outcome

To investigate the impact of insulin secretion on pregnancy outcome, we studied 102 patients at risk for glucose intolerance between 28 and 34 weeks of gestation. All patients had a 3-hour oral glucose tolerance test (OGTT, 100 g glucose), and glucose and insulin plasma levels were assayed: 32 patients had a gestational diabetes (GDM); 25 had an impaired gestational glycemic tolerance (IGGT), and 45 with normal OGTT constituted the control group. No significant difference between groups was seen for pregnancy outcome. Based on the mean +/- 2 SD of insulin secretion of the control group, IGGT/GDM patients were classified as normoinsulinemic (34 patients), hyperinsulinemic (17 patients), or hypoinsulinemic (6 patients). The hyperinsulinemic IGGT/ GDM group showed a greater incidence of pregnancy-induced hypertension (p < 0.03), while the percentile birth weight was significantly lower (p < 0.01) with respect to normo-hypoinsulinemic patients. Moreover a higher glucose/ insulin ratio was significantly related to birth weight (p < 0.01). Our results suggest an impact of insulin secretion on pregnancy outcome and support the importance of determining the insulinemic pattern in pregnant patients at risk for glucose intoleranc

Changes in fatty acids sebum composition during human menstrual cycle: possible relationships with fertile period

Changes in fatty acids sebum composition during human menstrual cycle: possible relationships with fertile perio

Indomethacin in vivo inhibits the enhancement of the progesterone secretion in response to gonadotrophin-releasing hormone by human corpus luteum

Different prostaglandins (PG) seem to have luteolytic or luteotrophic function in relation to the phases of life of the human corpus luteum and in-vitro studies demonstrate a luteotrophic function of PGE2, PGI2, PGD2. The present study evaluated the effect of an inhibitor of prostaglandin synthesis on the hypophyseal and luteal responses to gonadotrophin-releasing hormone (GnRH) in women during the mid-luteal phase. Twenty normal menstruating women participated in the study. Two different protocols were applied. After monitored ovulation (day 0), eight patients were treated with indomethacin for 7 days and 12 untreated patients served as controls. To evaluate luteal progesterone production, blood samples were taken every 15 min for 2 h basally and after a bolus of GnRH (25 micrograms i.v.); eight control patients were also treated with indomethacin for one day, and the endocrine study was repeated. The long-term administration of indomethacin significantly reduced basal as well as luteinizing hormone (LH)-stimulated progesterone production by the corpus luteum in respect to controls. Short-term administration failed to influence basal progesterone production, but abolished its secretory response to LH. A luteotrophic role for prostaglandins in human luteal function is suggeste

Human growth hormone enhances progesterone production by human luteal cells in vitro: evidence of a synergistic effect with human chorionic gonadotropin

OBJECTIVE: To examine the possible direct effect of human growth hormone (hGH) on basal and human chorionic gonadodotropin (hCG)-stimulated progesterone (P) production by cultured human luteal cells. DESIGN: Cultures of human luteal cells from early and midluteal phase. SETTING: All corpora lutea were obtained from the Obstetrics and Gynecology Department of the Catholic University, a public care center. PATIENTS, PARTICIPANTS: Twelve nonpregnant women between 35 and 47 years of age underwent surgery for various nonendocrine disorders such as leiomyomatosis. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. MAIN OUTCOME MEASURE: Luteal cells were incubated with or without hCG and/or hGH at different concentrations. RESULTS: Human growth hormone neither at 250 nor at 500 ng/mL increased basal P production, whereas from 1,000 ng/mL P concentration in media was significantly increased (P less than 0.05). The concomitant treatment with uneffective doses of hCG (6 and 12 ng/mL) and hGH (250 and 500 ng/mL) enhanced P production similarly to that obtained with the highest doses of hGH (1,000 ng/mL or more) or hCG (25 to 50 ng/mL) alone. CONCLUSIONS: These results indicate a direct effect of hGH on the luteal steroidogenesis in vitr

Insulin secretion in patients with gestational diabetes: relationship with pregnancy outcome

The authors observed that there is wide variability in insulin response to an oral glucose tolerance test in women developing carbohydrate intolerance during pregnancy. This variability ranges from a reduction of pancreatic islet function to a normal or exaggerated secretory pattern of insulin. Moreover the results also suggest that exaggerated insulin secretion and/or high insulin resistance may play a role in the regulation of gestational blood pressure and that a higher glucose/insulin ratio may be positively related to birth weight. Clearly, further studies are needed to investigate the impact of this metabolic situation on the optimization of the clinical control of glucose metabolism and fetal homeostasi

Effect of opiate receptor blockade on the insulin response to oral glucose load in polycystic ovarian disease

In order to test the hypothesis that endogenous opiates are at least partially responsible for hyperinsulinaemia in patients with polycystic ovarian disease (PCOD), the effect of naloxone (an opiate receptor blocker) on the insulin response to oral glucose load (OGTT) was studied in 20 women with PCOD and 17 control subjects at days 5-8 of their follicular phase. After fasting overnight for 10-12 h, each woman received an i.v. bolus injection (2 mg) of naloxone or an equal volume of saline infusion followed by a constant infusion of naloxone or saline solution at a rate of 8 ml/h (1 mg/h of naloxone) for 5 h. OGTT (75 g) was performed 1 h after the bolus injection. The naloxone study was performed 48 h after the saline study. Naloxone did not modify the insulin response to OGTT in either group. When the data were related to the insulin response, in PCOD hyperinsulinaemic patients, naloxone significantly reduced (P less than 0.02) the insulin response to OGTT without any change in glycaemic response curves. In control and PCOD normoinsulinaemic patients, naloxone did not change significantly either the glycaemia or the insulin levels after OGTT. No change of gonadotrophin and steroid secretion was found in any patient receiving naloxone. In conclusion, endogenous opiates may play a significant role in hyperinsulinaemia in PCO