Prostate cancer treatment still represents a not fully met medical need. Polyphenols, including stilbenes, are attractive clinical candidates due to their ability to not only block or inhibit initiation of carcinogenesis but also to reverse the promotional stages.
Research in the past unveiled that resveratrol down-regulates metastasis-associated protein 1 (MTA1) in prostate cancer. MTA1 over-expression is correlated with parameters that characterize tumor aggressiveness: lymph node metastasis, high tumor grades, and angiogenesis in various cancers. In human prostate tissues, a high MTA1 level is associated with hormone-refractory prostate cancer.
MTA1 is involved in protein deacetylation and gene-specific transcriptional regulation. Resveratrol-induced MTA1 degradation destabilizes the MTA1/HDAC/NuRD deacetylation complex leading to increased activation of tumor suppressor p53 in prostate cancer cells. Unfortunately due to resveratrol’s rapid metabolism and low bio-availability in the human body no clinical significance is expected from resveratrol use. This prompted the researchers in this study to search and test similar compounds with improved pharmacokinetics and therefore anti cancer potency.
Resveratrol was compared with six analogues in their ability to inhibit MTA1 expression and signaling. The investigation mainly focussed on the most potent analogue pterostilbene and its MTA1-mediated anticancer and anti-metastatic effects.
The team tested the effect both in vitro and in vivo by using prostate cancer xenografts implanted in mice.
The results showed that resveratrol and pterostilbene inhibited tumor growth, progression, metastasis and the involvement of MTA1-mediated signaling in cancer cell growth and metastasis. Especially pterostilbene had effects on proliferative and apoptotic indexes.
Higher serum levels of pterostilbene were detected compared to resveratrol in both EV and MTA1-knockdown groups. Previous studies have also shown higher bioavailability for pterostilbene which was attributed to the replacement of two hydroxy by methoxy groups making pterostilbene more lipophilic and more stable. In addition, pterostilbene’s half-life is several times longer than resveratrol’s. Better bioavailability of pterostilbene could explain its greater in vivo activity compared to resveratrol.
In summary, the study demonstrated mechanistic evidence of MTA1 as a potential therapeutic target in prostate cancer. MTA1 has the advantage of being sensitive to pharmacologically safe dietary compounds with pterostilbene the lead compound for potent target-specific treatment of MTA1-overexpressing prostate cancers.