Polysaccharide-K (PSK) increases p21WAF/Cip1 and promotes apoptosis in pancreatic cancer cells

Background: Polysaccharide-K (PSK, Krestin (R)) is a natural remedy and one of the most commonly used medicinal mushroom extracts. It has been used as oral adjuvant treatment in cancer therapy in Japan and other Asian countries for more than 40 years. PSK is thought to be an immune modulator, however, its antitumor actions remain undefined. The aim of the present study was to investigate underlying mechanisms by which PSK exerts its antitumor effects on malignant epithelial cells. Methods: Antitumor activities of PSK were evaluated on multiple human pancreatic adenocarcinoma cells in vitro. Cell viability, apoptotic pathways, cytokine expression and involvement of TLR2 and TLR4 were monitored by MIT, flow cytometry. Western blotting and protein arrays. Results: We demonstrate that PSK acts as a growth inhibitor for pancreatic cancer cells, known otherwise to be highly resistant to conventional chemotherapies. Pancreatic cancer cells can be protected against PSK-mediated growth inhibition by neutralizing antibodies against TLR2 and TLR4. The antiproliferative actions were associated with upregulated cell cycle regulatory p21(WAF)/(CiP1) and pro-apoptotic protein Bax levels, resulting in cell cycle arrest and induction of apoptosis. In addition, a significant growth inhibition and additive effect was observed with PSK and gemcitabine administered as combined treatment. Conclusion: While previous studies have emphasized the potential importance of PSK in immune activation, the present results uncover additional mechanisms on epithelial cells that may contribute to the antitumor effects provided by PSK as suggested by clinical observations. Copyright (C) 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.