Anti-metastatic activity of Acanthopanax senticosus extract and its possible immunological mechanism of action
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.
Section snippets
Preparation of Acanthopanax senticosus extract
The barks of Acanthopanax senticosus originated from China were purchased from a herbal medicine company (Daehyo Pharm., Korea). The barks were mixed with 20 volumes of distilled water, homogenized for 1 min and then stirred at 4 °C overnight. After centrifuge at 9000 rpm for 20 min, the supernatant was filtered with 0.2 μm pore sized filters and lyophilized. Finally, 5.5 g of the dried extract was obtained from 100 g of the barks of Acanthopanax senticosus. An appropriate amount of obtained brown
Inhibitory effect of GF100 on experimental lung metastasis
In order to investigate if GF100 has antitumor activity to inhibit tumor metastasis, we examined the prophylactic effect of GF100 on the experimental lung metastasis produced by colon26-M3.1 cells. Table 1 shows that i.v. administration of GF-100 (100–500 μg/mouse) 2 days before tumor inoculation significantly inhibited lung metastasis of colon26-M3.1 cells in a dose-dependent manner. However, the smaller amount of GF100 (20 μg/mouse) had no effect. Similarly, treatment with 100–500 μg/mouse of
Discussion and conclusions
Biological response modifier (BRM) has been thought to be a useful tool to suppress tumor growth and inhibit tumor metastasis (Suto et al., 1994, Yoo et al., 1994). In fact, various BRMs such as natural products involving oriental medicines, cytokines, synthetic adjuvants having biological activity to enhance host defense system have been applied to cancer immunotherapy (Suto et al., 1994, Schmeda-Hirschmann et al., 2001, Kang et al., 2002, Saiki, 2000). In many cases, BRMs activate
References (30)
- et al.
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look
Journal of Ethnopharmacology
(2000) - et al.
Panax ginseng and Eleutherococcus senticosus may exaggerate an already existing biphasic response to stress via inhibition of enzymes which limit the binding of stress hormones to their receptors
Medical Hypotheses
(2001) - et al.
Modulation of macrophage function activity by ethanolic extract of larvae of Holotrichia diomphalia
Journal of Ethnopharmacology
(2002) - et al.
Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation
Cell
(1991) - et al.
Immunomodulatory activity of Chilean Cyttaria species in mice with L5178Y lymphoma
Journal of Ethnopharmacology
(2001) - et al.
Ciwujianosides D1 and C1: powerful inhibitors of histamine release induced by anti-immunoglobulin E from rat peritoneal mast cells
Journal of Pharmacological Sciences
(1992) - et al.
Acanthopanax senticosus root inhibits mast cell-dependent anaphylaxis
Clinica Chimica Acta
(2001) - et al.
Prophylactic effect of Korean mistletoe (Viscum album coloratum) extract on tumor metastasis is mediated by enhancement of NK cell activity
International Journal of Immunopharmacology
(1998) - et al.
Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating monocytes: a new approach to cancer immunotherapy
Cancer Research
(1990) - et al.
Direct evidence for the role of LGL in the reduction of experimental metastasis
Journal of Immunology
(1985)
Compromised anti-tumor responses in tumor necrosis factor-alpha knockout mice
European Journal of Immunology
Constituents and pharmacological effects of Eucommia and Siberian ginseng
Acta Pharmacologica Sinica
Effect of Eleutherococcus senticosus on submaximal and maximal exercise performance
Medicine and Science in Sports and Exercise
Colorimetric method for determination of sugars and related substances
Analytical Chemistry
Cancer metastasis
British Medical Bulletin
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The authors equally contributed as corresponding authors to this study.