Researchers of the University of Mississippi Medical Center and the Schwartz College of Pharmacy and Health Sciences published a report showing positive findings regarding the effects of pterostilbene in aggressive human prostate cancer driven by a deregulated Pten/Akt pathway. The work was done in pre-clinical mouse models of prostate cancer and positive effects were found by both supplementation of pterostilbene in food as well as injection. The research adds more evidence to findings from a study in 2013 as well as other research that pterostilbene is a dietary compound with the potential to inhibit the overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) which is associated with the deregulated Pten/Akt pathway.
Although partial or complete loss of chromosome 10 in brain, bladder, and prostate cancers was identified as early as 1984, it was not until 1997 that a tumor suppressor gene was discovered at the “10q23.31 locus” named the phosphatase and tensin homolog (Pten). Pten is a nonredundant phosphatase (enzyme) that antagonizes the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, one of the most important and well-studied cancer promoting pathways. As Pten is the only known enzyme counteracting the PI3K/AKT pathway its somewhat logical that loss of PTEN has a significant impact on prostate cancer progression. Research has shown that loss of Pten occurs frequently in many advanced stage sporadic tumors, including ~60 % of advanced prostate cancers.
The researchers found that MTA1 levels were dramatically increased in prostate epithelial cells (both epithelial and reactive stroma). These significantly increased levels of MTA1 promote inflammation, tumorigenesis, EMT, angiogenesis and represses apoptosis. Inline with other studies the researchers confirmed this inverse relationship between MTA1 and Pten on the transcriptional level, and also identified MTA1 binding to Pten promoters. Downregulation of MTA1 therefore seems an attractive treatment target.
Two mouse models were used to test this hypothesis, Pten heterozygous (Pten+/f) and Pten-null (Ptenf/f) due to their close resemblance to human prostate disease and an intact immune system. The second model represents best progression stage of human prostate cancer.
The Pten+/f mice were fed pterostilbene (100 mg/kg diet) for 8–10 months. All mice (control and pterostilbene fed) by 8–10 months of age developed high grade PIN (precancerous condition) however mice on the pterostilbene diet showed 50% reduction in the number of glands involved and more favorable, normal ductal structures and higher PTEN protein expression.
In the second “progression” model the Pten f/f mice were treated with daily pterostilbene (10 mg/kg bw) injections. It was found that mice on pterostilbene diet had clearly smaller prostates relative to controls. Overall, 64% of the mice not receiving pterostilbene developed preinvasive or invasive adeno-carcinoma whereas daily 10 mg/kg pterostilbene treatment reduced the incidence of adeno-carcinomas to 12% and halted the progression at PIN stage (precancerous condition).
Finally it was investigated whether pterostilbene truly reached the prostate tissues. The researchers found accumulation of pterostilbene in the prostates by diet and injection method and as one may expect, more accumulation when injected.
For completion and perspective we calculate the Human Equivalent Dose (HED) for the diet given to the Pten+/f mice. The FDA has specified guidelines for this conversion to Human Equivalent Dose (HED). Using this guideline 100 mg/kg dosing in mice translates into a HED of approx. 8mg/kg. Or into 560mg daily dose for a person weighing 70kg. Typical supplements on the market have serving sizes of 50 or 100mg with several studies indicating that pterostilbene is safe also at higher dosing levels.