Ginsenoside Rg1 Drives Stimulations of Timosaponin AIII‐Induced Anticancer Effects in Human Osteosarcoma Cells

Abstract

A ginsenoside Rg1 is an active compound extracted from the stem and/or root of ginseng. Rg1 has been known to affect various human organ systems including the immune, cardiovascular, and nervous systems with its pharmacological effects. Timosaponin AIII (TA3) is a type of spirostanol saponins that are the major compounds of Anemarrhena asphodeloides. TA3 exerts anticancer effects in various human cancers, and the effects include attenuations of cancer cell migration and induction of apoptosis. In this study, I report that Rg1 drives the stimulation of TA3-induced cytotoxic effects in MG63 human osteosarcoma cells. Rg1 stimulates TA3-induced apoptosis in MG63 cells via selective intensification of caspase-3 activation. Rg1 and TA3 synergistically induced antimetastatic effects such as attenuation of MG63 cell migration and inhibitions of matrix metalloproteinases (MMP-2 and MMP-9). Rg1 and TA3 synergistically suppressed JNK, p38, ERK, β-catenin, and CREB signaling, which are key regulators of cancer metastasis. Finally, the synergistic anticancer effects of Rg1 and TA3 were also observed in U2OS human osteosarcoma cells, and this may indicate that the synergy is not limited specifically to MG63 cells. The results presented here suggest that the combinatorial use of Rg1 and TA3 may be a promising way to develop an effective antiosteosarcoma agent.

Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides

“…Even though there are numerous molecules proposed to be targets for suppressing metastatic abilities of cancers and inflammatory diseases, MMPs are one of the most intriguing ones because both their ECM degradation and non-enzymatic modes of action considerably contribute to metastasis and immune responses. Since ginsenosides’ MMP suppression had synergy with a few known compounds, co-treatment with other chemicals including MMP inhibitors may also exhibit promising results in the future [ 67 , 85 , 108 , 128 ]. This escalates the value of ginsenosides as promising anti-cancer and anti-inflammatory agents to be further developed and modified.…”

“…Furthermore, Rg1 can exert synergistic MMP-inhibiting effects with other drugs. A recent study showed that Rg1 could intensify anti-metastatic effects of Timosaponin AIII, an anti-cancer steroid saponin, in MG63 and U2OS osteosarcoma cells [ 67 ]. In particular, gelatin cleavage by MMP-2 and MMP-9 were remarkably reduced via transcriptional regulation when cells were exposed to both Timosaponin AIII and Rg1.…”

“…In particular, gelatin cleavage by MMP-2 and MMP-9 were remarkably reduced via transcriptional regulation when cells were exposed to both Timosaponin AIII and Rg1. Repressive effects of Timosaponin AIII (6 μM) on JNK, p38 and ERK were significantly strengthened by the combination with Rg1 (250 μM) [ 67 ].…”

“… Summary of activities of ginsenoside Rg1. Structure of Rg1 and its effects on MMPs and/or signalings [ 61 , 66 , 67 , 68 , 70 , 71 ]. …”

Ultrahigh‐performance liquid chromatography coupled to ion mobility quadrupole time‐of‐flight mass spectrometry profiling and unveiling the transformation of ginsenosides by the dual conditions of citric acid and high‐pressure steaming

“…Ginseng, the root of Panax ginseng C. A. Meyer, has been used for thousands of years as a traditional Chinese medicine (TCM) in Asian countries to strengthen immunity, supply nutrition, and decrease fatigue. Ginsenosides are the major active components in ginseng, having a variety of bioactive and pharmacological activities, including anticancer, 1,2 antitumor, 3,4 antidiabetic, 5,6 antihypertensive, 7 antifatigue, 8 and antiaging effects 9 . More than 500 kinds of ginsenosides have been identified from ginseng and related herbs 10,11 .…”