Rapatar, a nanoformulation of rapamycin, decreases chemically-induced benign prostate hyperplasia in rats

Abstract

Benign prostatic hyperplasia (BPH) is the most common age-related disease in men. Here we tested the efficacy of Rapatar, a micellar nanoformulation of rapamycin, in two rat models of BPH: testosterone-induced and sulpiride-induced hyperplasia in ventral lobes and lateral/dorsal lobes, respectively. We found that Rapatar prevented hypertrophic and hyperplastic abnormalities and degenerative alterations in both BPH models. Rapatar normalized weight of the lateral lobes in sulpiride-induced BPH, the most relevant animal model of human BPH. Unlike Finasteride, a standard therapy of BPH, Rapatar reduced inflammation caused by sulpiride. No obvious side effects of Rapatar were detected. Our data provide a rationale for clinical trials of Rapatar in patients suffering from BPH.

Integrative genomic, transcriptomic, and epigenomic analyses of benign prostatic hyperplasia reveal new options for therapy

“…To nominate potential subtype specific therapeutic options, we utilized the Connectivity Map 40, 41 analysis ( Figure 4A and Table S13), which uses transcriptional expression data to probe relationships between diseases, cell physiology, and therapeutics. Strikingly, we found 50% of nominated compounds in BPH-A subgroup were related to inhibition of mTOR signaling ( Figure 4B), and the subgroup enrichment of mTOR signaling was validated in two independent cohorts ( Figure 4C), consistent with prior isolated reports in model systems 42,43,44 . To interrogate the potential effect of mTOR treatment on the prostate, we examined prostate size on cross-sectional imaging in patients taking mTOR inhibitors.…”

Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats

“…These discrepancies may point to the need of targeting rapamycin-treatment to an animal model that already manifests metabolic dysregulation and aging phenotypes. Evidence supporting this hypothesis includes rapamycin treatment-related decrease in obesity and prevention of weight gain in rodents and humans [ 25 - 32 ] as well as downregulation of fasting levels of phosphorylated S6 (p-S6; a marker of mTORC1 activity) in mice on high-fat diet [ 33 , 34 ]. Given that high fasting levels of p-S6 is indicative of increased geroconversion from quiescence to senescence [ 35 , 36 ] and the suppression of geroconversion by rapamycin prevents age-related diseases in mammals [ 34 ], the observed beneficial effects on age-related declines in muscle strength and aerobic capacity among LCR rats exhibiting metabolic dysregulation may in fact result from rapamycin-induced suppression of “systemic hyper-functions (e.g.…”

Elevated expression of HIF-lα in actively growing prostate tissues is associated with clinical features of benign prostatic hyperplasia

“…The mechanism might be the blockade of mammalian target of rapamycin (mTOR)-dependent increase in HIF-1α and HIF-2α protein levels and VEGF upregulation. In addition, rapatar, a nanoformulation of rapamycin, has been demonstrated to decrease chemically-induced BPH in two rat models, without obvious side effects [ 32 ]. Moreover, increasing studies have demonstrated that rapamycin prolongs life span and prevents age-related diseases in mice [ 33 - 35 ].…”