Novel Lignan and Stilbenoid Mixture Shows Anticarcinogenic Efficacy in Preclinical PC-3M-luc2 Prostate Cancer Model

Emrah Yatkin,Sari I Mäkelä,Niina M Saarinen,Tero Aittokallio,Annika Smeds,Bjarne Holmbom,Christer Eckerman,Teemu D Laajala,Lauri Polari,Rajesh Agarwal

doi:10.1371/journal.pone.0093764

Abstract

Prostate cancer is the most common cancer of men in the Western world, and novel approaches for prostate cancer risk reduction are needed. Plant-derived phenolic compounds attenuate prostate cancer growth in preclinical models by several mechanisms, which is in line with epidemiological findings suggesting that consumption of plant-based diets is associated with low risk of prostate cancer. The objective of this study was to assess the effects of a novel lignan-stilbenoid mixture in PC-3M-luc2 human prostate cancer cells in vitro and in orthotopic xenografts. Lignan and stilbenoid –rich extract was obtained from Scots pine (Pinus sylvestris) knots. Pine knot extract as well as stilbenoids (methyl pinosylvin and pinosylvin), and lignans (matairesinol and nortrachelogenin) present in pine knot extract showed antiproliferative and proapoptotic efficacy at ≥40 μM concentration in vitro. Furthermore, pine knot extract derived stilbenoids enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis already at ≥10 μM concentrations. In orthotopic PC-3M-luc2 xenograft bearing immunocompromized mice, three-week peroral exposure to pine knot extract (52 mg of lignans and stilbenoids per kg of body weight) was well tolerated and showed anti-tumorigenic efficacy, demonstrated by multivariate analysis combining essential markers of tumor growth (i.e. tumor volume, vascularization, and cell proliferation). Methyl pinosylvin, pinosylvin, matairesinol, nortrachelogenin, as well as resveratrol, a metabolite of pinosylvin, were detected in serum at total concentration of 7−73 μM, confirming the bioavailability of pine knot extract derived lignans and stilbenoids. In summary, our data indicates that pine knot extract is a novel and cost-effective source of resveratrol, methyl pinosylvin and other bioactive lignans and stilbenoids. Pine knot extract shows anticarcinogenic efficacy in preclinical prostate cancer model, and our in vitro data suggests that compounds derived from the extract may have potential as novel chemosensitizers to TRAIL. These findings promote further research on health-related applications of wood biochemicals.

Highlights

Prostate cancer (PCa) is the most common cancer of men in North America, Western Europe, Eastern Europe, and Scandinavia
We have demonstrated anticarcinogenic effects of the Scots pine knot extract (PKE), a mixture rich in lignans and stilbenoids, in vitro and in vivo in an orthotopic PCa xenograft model
Our results show that pine knotwood extract (PKE), as well as its main lignan and stilbenoid components are antiproliferative and proapoptotic in PC-3M-luc2 cells in vitro

Summary

Introduction

Prostate cancer (PCa) is the most common cancer of men in North America, Western Europe, Eastern Europe, and Scandinavia. The long natural history of PCa presents a relatively wide time window for dietary or pharmacological interventions that could manifest as reduction in incidence, recurrence, morbidity or progression of the disease [1]. Trees are an abundant source of phenolic compounds, structurally identical or similar to those in edible plants [5]. These compounds can be isolated from wood by hydrophilic extraction after removing the lipophilic extractives by hexane extraction [6]. Wood-derived extracts are a cost-effective source of natural phenolic compounds, and an attractive option for the development of novel health-promoting products

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