Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters








Database
Language
Publication year range
1.
Int J Radiat Oncol Biol Phys ; 115(2): 317-326, 2023 02 01.
Article in English | MEDLINE | ID: mdl-35907513

ABSTRACT

BACKGROUND: Patients with prostate cancer undergoing treatment with radical radiation therapy (RT) plus androgen deprivation therapy (ADT) experience a constellation of deleterious metabolic and anthropometric changes related to hypogonadism that are associated with increased morbidity and mortality. We assessed the effect of metformin versus placebo to blunt the adverse effects of ADT on body weight, waist circumference, and other metabolic parameters. METHODS AND MATERIALS: This phase 2, multicenter, randomized controlled trial (RCT) randomized normoglycemic men with locally advanced prostate cancer receiving radical RT and ADT (18-36 months) in a 1:1 ratio to receive metformin 500 mg by mouth 3 times a day (for 30-36 months) versus identical placebo. RESULTS: From December 2015 to October 2019, 83 men were randomized with median follow-up of 23 months. Baseline mean body mass Index (BMI) of the cohort was 30.2 (range 22.2-52.5). Change in mean weight relative to baseline was lower among men who received metformin compared with placebo at 5 months (-1.80 kg, P = .038), but was not significant with longer follow-up (1 year: +0.16 kg, P = .874). Although participants on ADT had increases in waist circumference in both study arms, metformin did not significantly reduce these changes (1 year: +2.79 cm (placebo) versus +1.46 cm (metformin), P = .336). Low-density lipoprotein (LDL) cholesterol was lower in the metformin arm (-0.32 mmol/L) compared with the placebo arm (-0.03 mmol/L) at 5 months (P = .022), but these differences were not significant with longer follow-up (1 year: -0.17 mmol/L vs -0.19 mmol/L, P = .896). There were no differences in HbA1C, triglyceride, high-density lipoprotein (HDL) cholesterol, and total cholesterol by study arm. CONCLUSIONS: Men receiving radical RT and ADT gained weight and had increases in waist circumference over time that metformin did not significantly mitigate. Although this study did not observe any preventive effect of metformin on the anthropometric and metabolic complications of ADT, metformin continues to be studied in phase 3 RCTs in this patient population to assess its potential antineoplastic effects.


Subject(s)
Metformin , Prostatic Neoplasms , Male , Humans , Metformin/therapeutic use , Androgens , Androgen Antagonists/adverse effects , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/radiotherapy , Cholesterol/therapeutic use
2.
Mol Cell Neurosci ; 47(2): 145-53, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21463685

ABSTRACT

Oxygen (O2) tension has emerged as a major regulator of stem cell (SC) biology. Low O2 concentrations that are toxic to mature cells can confer advantage to stem and early progenitors, while superoxide stress remains a constant threat in aerobic biology and may be partially avoided through sequestration of SCs in the relatively hypoxic stem or regenerative niche. Using primary retina-derived retinal progenitor cells (RPCs) and the R28 progenitor cell line in vitro, we show that RPCs are sensitive to hydrogen peroxide (H2O2) induced damage and resistant to moderate levels of low oxygen stress (1% O2). Under hypoxic conditions, multipotent RPCs upregulate Epo receptors, and Epo, along with insulin, protects against both superoxide- and severe hypoxia- (0.25% O2) induced apoptosis through activation of the canonical PI3K/Akt/mTOR pathway. This survival advantage is sensitive to inhibitors of PI3K and mTOR. We further demonstrate phosphorylation of the p70S6 ribosomal kinase, a downstream mediator of PI3K/Akt/mTOR and translational activator. Overall, these data confirm that RPCs are sensitive to superoxide stress and resistant to hypoxia and that this resistance is mediated in part by Epo. They further suggest that manipulation of RPCs ex vivo prior to ocular delivery, or the in vivo delivery of exogenous survival factors at the time of cell implantation, could enhance the success of regenerative therapies aimed to restore sight.


Subject(s)
Cell Hypoxia/physiology , Cell Survival/physiology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Retina/cytology , Stem Cells/physiology , Superoxides/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Cells, Cultured , Erythropoietin/metabolism , Erythropoietin/pharmacology , Hydrogen Peroxide/pharmacology , Insulin/metabolism , Mice , Oxidants/pharmacology , Phosphorylation , Signal Transduction/drug effects , Signal Transduction/physiology , Stem Cells/cytology , Stem Cells/drug effects , Stress, Physiological
SELECTION OF CITATIONS
SEARCH DETAIL