Disruption of cellular energy balance by suramin in intact human prostatic carcinoma cells, a likely antiproliferative mechanism.

The antiparasitic drug, suramin, has antiproliferative effects in human carcinoma cells. It has been suggested that this occurs through blockade of growth factor-receptor interactions. Three types of evidence that suramin rapidly inhibits cellular respiration or disrupts cellular energy balance in intact cells of the human prostate carcinoma cell line, DU145, are presented. Beginning at approximately 10(-4) M, suramin rapidly causes dose-dependent inhibition of tetrazolium conversion by mitochondrial dehydrogenases in intact cells, demonstrating an inhibition of respiration. This effect is reversed by exchange with suramin-free media but not by pretreatment with serum, epidermal growth factor, insulin-like growth factor I, acidic and basic fibroblast growth factors, or calcium. Rhodamine 123 (10 micrograms/ml) uptake by mitochondria in intact DU145 cells is inhibited in the presence of 10(-3) M suramin. Treatment with 10(-4)-10(-3) M suramin causes the loss of rhodamine 123 from cells with mitochondria prestained with rhodamine 123, indicating that suramin is acting as an ionophore or respiratory poison. Also shown by electron microscopy are progressive toxic changes in mitochondria of DU145 cells within 1 h after treatment with 10(-4) M suramin. These data indicate that in intact DU145 cells 10(-4) M suramin rapidly disrupts cellular energy balance or respiration as seen by three studies of mitochondrial state. Disruption of energy balance or respiration represents a likely antiproliferative mechanism, as is thought to be a primary mechanism for the action of suramin in parasitic diseases. This proposed mechanism of action for suramin can explain the most prominent observed clinical toxicities of nephrotoxicity, adrenal toxicity, coagulopathy, and demyelinating neuropathy.     

Cytotoxic lipid esters from Peucedanum ledebourielloides

Two cancer cell growth inhibitory esters, 1,2-dipalmitoyl-3-glucosyl glycerol (1) and 1,6-dihydroxy-hexane-bis-palmitoyl ester (2), together with arachidic acid-2-hydroxy-glycerol ester, daucosterol, and oleanolic acid, were isolated from the roots of Peucedanum ledebourielloides (Apiaceae family). The structures were determined by spectroscopic analyses. The esters 1 and 2 displayed significant activity against the SGC-7901, HT-29, and HL-60 cancer cell lines.     

Exercise and global well-being in community-dwelling adults with fibromyalgia: a systematic review with meta-analysis

Background  

Exercise has been recommended for improving global-well being in adults with fibromyalgia. However, no meta-analysis has determined the effects of exercise on global well-being using a single instrument and when analyzed separately according to intention-to-treat and per-protocol analyses. The purpose of this study was to fill that gap.     

Acetylcholinesterase inhibitors may improve myelin integrity.

Recent clinical trials have revealed that cholinergic treatments are efficacious in a wide spectrum of neuropsychiatric disorders that span the entire human lifespan and include disorders without cholinergic deficits. Furthermore, some clinical and epidemiological data suggest that cholinergic treatments have disease modifying/preventive effects. It is proposed that these observations can be usefully understood in a myelin-centered model of the human brain. The model proposes that the human brain's extensive myelination is the central evolutionary change that defines our uniqueness as a species and our unique vulnerability to highly prevalent neuropsychiatric disorders. Within the framework of this model the clinical, biochemical, and epidemiologic data can be reinterpreted to suggest that nonsynaptic effects of cholinergic treatments on the process of myelination and myelin repair contributes to their mechanism of action and especially to their disease modifying/preventive effects. The ability to test the model in human populations with safe and noninvasive imaging technologies makes it possible to undertake novel clinical trial efforts directed at primary prevention of some of the most prevalent and devastating of human disorders.