Biological mechanism and clinical effect of protein-bound polysaccharide K (KRESTIN(®)): review of development and future perspectives

Abstract

The mechanism of action of protein-bound polysaccharide K (PSK; KRESTIN(®)) involves the following actions: (1) recovery from immunosuppression induced by humoral factors such as transforming growth factor (TGF)-β or as a result of surgery and chemotherapy; (2) activation of antitumor immune responses including maturation of dendritic cells, correction of Th1/Th2 imbalance, and promotion of interleukin-15 production by monocytes; and (3) enhancement of the antitumor effect of chemotherapy by induction of apoptosis and inhibition of metastasis through direct actions on tumor cells. The clinical effectiveness of PSK has been demonstrated for various cancers. In patients with gastric or colorectal cancer, combined use of PSK with postoperative adjuvant chemotherapy prolongs survival, and this effect has been confirmed in multiple meta-analyses. For small-cell lung carcinoma, PSK in conjunction with chemotherapy prolongs the remission period. In addition, PSK has been shown to be effective against various other cancers, reduce the adverse effects of chemotherapy, and improve quality of life. Future studies should examine the effects of PSK under different host immune conditions and tumor properties, elucidate the mechanism of action exhibited in each situation, and identify biomarkers.

Fig. 1

Tumor microenvironment and actions of PSK. ① Suppressed production or neutralization of immunosuppressive factors. ② Activation of immune cells and regulation of cytokine production. ③ Direct action on tumor cells [induction of apoptosis, enhanced expression of major histocompatibility complex (MHC) class I antigen]. Adapted from Fujii [11]

Fig. 2

Effect of oral administration of PSK on apoptosis of circulating T cells induced by the anticancer drug S-1 in gastric cancer patients. Adapted and modified from Kono et al. [27]

Fig. 3

Schematic representation of the antitumor immune responses and actions of PSK. Tumor cells or their fragments are taken up by APCs. Antigen peptides bind to MHC class I or II on the APCs. The antigen peptides on MHC class I molecules activate naïve CD8⁺ T cell, whereas the antigen peptides on MHC class II molecules activate naïve CD4⁺ T cells (T-helper cell precursors). T-helper cell precursors differentiate into Th1 and Th2 cells. Th1 cells produce cytokines, including IL-2 and IFN-γ. These cytokines induce proliferation and activation of tumor antigen-specific CTLs, activation of NK cells and macrophages, and induction of LAK cells

Fig. 4

Effect of PLCC plus PSK on 15-year OS in patients with advanced gastric cancer after curative resection. Adapted and modified from Maehara et al. [77]

Fig. 5

Effect of adjuvant immunochemotherapy with PSK on 5-year overall survival in patients with T2 or T3 gastric cancer after curative resection. Adapted and modified from Nakazato et al. [83]

Fig. 6

Meta-analysis of the effect of adjuvant immunochemotherapy with PSK on OS in patients with gastric cancer after curative resection. JMTC, Japanese Foundation for Multidisciplinary Treatment of Cancer; MF mitomycin C plus tegafur, MHCFU mitomycin C plus HCFU, MFU mitomycin C plus 5-fluorouracil, MT mitomycin C plus tegafur, T tegafur. Adapted from Oba et al. [85]

Fig. 7

Meta-analysis of the effect of adjuvant immunochemotherapy with PSK on OS in patients with colorectal cancer after curative resection. Adapted from Sakamoto et al. [93]

Fig. 8

PSK-stimulated activation of blood lymphocytes in healthy volunteers and cancer patients (a). Effects of adjuvant immunochemotherapy with PSK on 10-year OS in gastric cancer (b) and colorectal cancer (c) patients with low or high PSK-induced lymphocyte activation level. The increase in DNA synthesis of lymphocytes was defined as ratio of the level of PSK-treated lymphocytes versus PSK-non-treated lymphocytes. Asterisk adjusted by gender, age, Dukes’ stage, tumor size, lymphatic vessel invasion, and venous invasion. Adapted from Sugimachi et al. [115] and Yoshinaga et al. [116]