Bioactivity and prostate tissue distribution of metformin in a preprostatectomy prostate cancer cohort

Abstract

Metformin has recently been shown to have potential to reduce prostate cancer risk. We conducted a randomized, double-blind, placebo-controlled trial to determine the modulating effects of metformin on tissue and systemic biomarkers of drug activity and its distribution into the prostate tissue. Twenty patients with prostate cancer scheduled to undergo prostatectomy were randomly assigned to receive either extended-release metformin or placebo for a median of 34 days before surgery. Prostatectomy and serum samples were analyzed for metformin concentrations, serum biomarkers of drug activity (prostate-specific antigen, insulin, insulin-like growth factor-1, insulin-like growth factor binding protein 3, sex hormone-binding globulin, and testosterone) and tissue biomarkers of proliferation, apoptosis, cell cycle regulation, and mTOR inhibition. For participants in the metformin arm, the prostate tissue and serum metformin concentrations ranged from 0.88 to 51.2 μg/g tissue and from not detectable to 3.6 μg/ml, respectively. There were no differences between the two groups in either the postintervention tissue biomarker expression in the prostatectomy tissue or pre to postintervention changes in serum biomarkers. We conclude that metformin distributes to human prostate tissue, suggesting that metformin could exert its effects directly on tissue targets. However, there was no difference in tissue and systemic drug effect biomarkers between the two treatment arms. Future studies with longer intervention duration and larger sample size should be considered in order to evaluate the potential of metformin for prostate cancer prevention.

Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability

“…However, important issues and concerns about this off-label activity are still unsolved. In particular, extremely high drug concentrations (within the mM range) are required to induce antitumor effects in in vitro studies, although in vivo metformin intratumoral concentrations were reported to be several fold higher than in plasma ( Nguyen et al, 2017 ; Baldassari et al, 2018 ). It was therefore proposed that protracted in vivo treatment using clinically reachable doses, can possibly induce antitumor effects ( Gritti et al, 2014 ).…”

Metformin and sodium dichloroacetate effects on proliferation, apoptosis, and metabolic activity tested alone and in combination in a canine prostate and a bladder cancer cell line

“…In a pre-prostatectomy study of human prostate cancer patients, the serum and prostate tissue concentration of metformin was determined. After 4–12 weeks of daily administration, serum concentrations increased from undetectable to 3.6 μg/mL, and prostate tissue concentrations of 0.88 to 51.2 μg/g were measured [ 83 ]. The observed pharmacokinetics of metformin in dogs seemed to be comparable to the pharmacokinetics reported for cats and humans [ 84 ].…”

Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions

“…Serum and saliva metformin concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS; ref. 48 ). Briefly, an aliquot of serum or saliva was mixed with the internal standard, phenformin.…”