Anti-metastatic activity of Acanthopanax senticosus extract and its possible immunological mechanism of action

Abstract

Antitumor and immunomodulatory activities of an aqueous extract (GF100) of Acanthopanax senticosus were examined. In experimental lung metastasis of colon26-M3.1 carcinoma cells, intravenous (i.v.) administration of GF100 2 days before tumor inoculation significantly inhibited lung metastasis in a dose-dependant manner. The i.v. administration of GF100 also exhibited the therapeutic effect on tumor metastasis of colon26-M3.1 cells, when it was injected 1 day after tumor inoculation. In an in vitro cytotoxicity analysis, GF100 at the concentration up to 1000 μg/ml did not affect the growth of colon26-M3.1 cells. In contrast, GF100 enhanced the responsiveness to a mitogen, concanavalin A (ConA), of splenocytes in a dose-dependent manner. Peritoneal macrophage stimulated with GF100 produced various cytokines such as IL-1β, TNF-α, IL-12 and IFN-γ in an in vitro experiment. The macrophages obtained from the mice which were injected with GF100 (500 μg) 3 days before the assay showed significantly higher tumoricidal activity against tumor cells than that of the untreated macrophages. In addition, the i.v. administration of GF100 significantly augmented NK cytotoxicity to Yac-1 cells. The depletion of NK cells by injection of rabbit anti-asialo GM1 serum completely abolished the inhibitory effect of GF100 on lung metastasis of colon26-M3.1 cells. These data suggest that GF100 has antitumor activity to inhibit tumor metastasis prophylactically as well as therapeutically, and its antitumor effect is associated with activation of macrophages and NK cells.

Introduction

Acanthopanax senticosus, also called the “Siberian Ginseng” or “Eleutherococcus senticosus”, has been well known to be prophylactic for various diseases such as chronic bronchitis, hypertension and ischemia (Yi et al., 2001). Acanthopanax senticosus is also known to be effective for reducing many kinds of stress (Gaffney et al., 2001) or fatigue (Dowling et al., 1996). Today this oriental herb is called ‘adatogen’ in the US (Davydov and Krikorian, 2000). Recently, Davydov and Krikorian (2000) reported that the herb included various compounds such as acanthosides, eleutherosides, senticoside, triterpenic saponin, flavon, vitamins and minerals, and they are related to its diverse biological activities. Interestingly, many investigators demonstrated two contrary views on the immunomodulatory effect of Acanthopanax senticosus: the stimulation (Schmeda-Hirschmann et al., 2001, Schmolz et al., 2001) and the suppression (Jeong et al., 2001, Yi et al., 2001, Umeyama et al., 1992) of immune responses. In fact, the stem of the herb has been clinically used for treatment of allergy in Korea. However, the precise mechanisms related to its immunomodulatory activities are still unclear.

It is well known that most death caused by cancer are not due to primary tumor but the dissemination of tumor cells to secondary sites by a series events known to collectively as the metastatic cascade (Fidler, 1991, Liotta et al., 1991). Many experimental studies and clinical trials showed that natural immunity played an important role in blocking of metastasis from primary tumors (Schantz et al., 1987). Among various immune-related cells, NK cells and macrophages were thought to be the relevant effectors responsible for the natural immunity against tumors (Barlozzari et al., 1985, Andreesen et al., 1990). Thus, it is possible that the functional activation of NK cells and macrophages elicit the suppression of tumor growth as well as the inhibition of tumor metastasis. Indeed, it was reported that activation of NK cells and macrophages by plant extracts could control the growth of tumor cells and their metastasis (Yoon et al., 1998, Saiki, 2000).

In this study, we investigated the anti-tumor activity of the aqueous extract (GF100) of Acanthopanax senticosus in respect to the prophylactic and therapeutic inhibition of lung metastasis of colon26-M3.1 carcinoma cells using experimental metastasis model in syngeneic mice, and analyzed the involvement of activation of NK cells and macrophages in its antimetastatic effect against tumors.