Suppression of metastasis of intravenously-inoculated B16/F10 melanoma cells by the novel ginseng-derived ingredient, gintonin: Involvement of autotaxin inhibition

Abstract

Ginseng has been used for cancer prevention. However, little is known about its active components and the molecular mechanisms underlying its effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin. Gintonin contains approximately 9.5% LPA, mainly LPA C18:2. Autotaxin (ATX) is responsible for metastasis by overproducing LPA in cancers. However, LPA, particularly LPA C18:2, is a strong negative feedback ATX inhibitor. It is unknown whether gintonin inhibits ATX activity and whether gintonin‑induced ATX inhibition is coupled with antimetastatic activity. In this study, we examined whether gintonin and LPA C18:2 inhibit ATX activity and metastasis‑related cellular activities in melanoma cells. We found that gintonin and LPA C18:2 inhibited the purified and secreted ATX activity from melanoma cells in a concentration‑dependent manner. Gintonin also inhibited cell migration with a minimal inhibition of cell growth. The oral administration of gintonin or LPA C18:2 inhibited lung metastasis induced by tail‑vein inoculations of melanoma cells. Moreover, the oral administration of gintonin significantly suppressed the tumor growth induced by subcutaneous grafts of melanoma cells. A histological analysis showed that the oral administration of gintonin reduced tumor necrosis, the pleomorphism of tumor cells, tumor cell mitosis and angiogenesis. The present study demonstrates that the gintonin‑induced inhibition of ATX activity may be the molecular basis of ginseng‑induced antimetastatic and antitumor activities.

Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain

“…In this regard, the humanized monoclonal antibody, anti-LPA B3, that targets LPA, is currently under investigation (Crack et al, 2014;Goldshmit et al, 2012). An alternative approach may be to target the enzyme ATX (Gierse et al, 2010;Gupte et al, 2011;Hwang et al, 2013), which contributes to LPA production. There are currently several ATX inhibitors in pre-clinical studies, although none are exclusive for NP.…”

“…PF-8380 is a specific inhibitor that reduces inflammatory hyperalgesia in rats within 3h (Gierse et al, 2010). Other ATX inhibitors, such as 4PBPA (Gupte et al, 2011), Gintonin (Hwang et al, 2013) and ONO-8430506 (Benesch et al, 2014) are indicated for cancer, although they may also have effects on NP (see Table 1). The first oral therapy developed for MS, i.e.…”

Preparation of a Monoclonal Antibody against Gintonin and Its Use in an Enzyme Immunoassay

“…7,13) In addition, gintonin inhibits autotaxin activity to suppress metastasis. 8) However, a method for quantifying the amount of gintonin in ginseng has not been developed. In the present study, we produced a monoclonal antibody against gintonin and developed an EIA for gintonin quantitation in ginseng and ginseng products.…”

“…2,3,5,6) The gintonin-mediated [Ca 2+ ] i transient is coupled to the regulation of Ca 2,7) Oral administration of gintonin elicits anti-Alzheimer's disease effects in vivo by activating the non-amyloidogenic pathway through LPA receptors and induces anti-metastatic effects by inhibiting autotaxin activity. 7,8) Biochemical analysis has shown that gintonin consists of carbohydrates, lipids, and proteins.…”

“…Gintonin, but not ginsenosides, induces an intracellular free calcium concentration ([Ca 2,7) Oral administration of gintonin elicits anti-Alzheimer's disease effects in vivo by activating the non-amyloidogenic pathway through LPA receptors and induces anti-metastatic effects by inhibiting autotaxin activity. 7,8) Biochemical analysis has shown that gintonin consists of carbohydrates, lipids, and proteins.2) The protein component of gintonin consists of ginseng major latex-like protein 151 (GLP) and ginseng ribonuclease-like storage protein (GSP). …”