Cancer Letters

Cancer Letters

Volume 144, Issue 1, 20 September 1999, Pages 39-43
Cancer Letters

Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin

https://doi.org/10.1016/S0304-3835(99)00188-3Get rights and content

Abstract

The in vitro antitumor activity of a novel ginseng saponin metabolite, 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol (IH-901), was examined against four human cancer cell lines and one subline resistant to cisplatin (CDDP). The growth inhibitory activity of the compound was estimated by MTT tetrazolium assay. The mean concentrations of IH-901 needed to inhibit the proliferation of the cells by 50% (IC50) were 24.3, 25.9, 56.6 and 24.9 μM against human myeloid leukemia (HL-60), pulmonary adenocarcinoma (PC-14), gastric adenocarcinoma (MKN-45) and hepatoma (HepG2) cell lines, respectively. These values are higher than that of CDDP. In the CDDP-resistant PC/DDP cell line, the IC50 values of IH-901 and CDDP were 20.3 and 60.8 μM, respectively. These results suggest that IH-901 is not cross-resistant to CDDP in this cell line and could be a candidate for the treatment of CDDP resistant pulmonary cancer.

Introduction

Ginseng radix, the root of Panax ginseng C.A. Meyer, has been used as a medicinal plant in Asian countries, and now it is used worldwide for preventive and therapeutic purposes. Among the diverse constituents of ginseng, saponins have been found to be the major components responsible for its biochemical and pharmacological actions. Recently, novel ginseng saponin metabolites formed by the human intestinal bacteria were found and their antitumor activity has been proposed [1]. Prevotella oris, which is found in 79% of the human fecal specimens, hydrolyses ginsenoside Rb1 and Rd to 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol (IH-901). Since IH-901 is one of the metabolites detected in blood after the oral administration to mice of ginsenoside Rb1, it is speculated that IH-901 is most likely the major form of protopanaxadiol saponin absorbed from the intestine [2]. The hypothesis that IH-901 may be the active metabolite responsible for the anticarcinogenic effect of ginseng saponins has prompted several groups to investigate the pharmacological effects of IH-901. For instance, Wakabayashi et al. reported that the antimetastatic effects of ginseng saponins are mediated by this metabolite [3]. They also proposed that the induction of apoptotic cell death of highly metastatic B16-BL6 mouse melanoma cells by the ginseng saponin metabolite probably leads to antimetastatic as well as antitumor activity in vivo [4].

Cisplatin (CDDP) is one of the most effective antitumor agents for the treatment of many types of cancer in the clinic, both as a single agent and in combination with other cytostatics [5]. However, the development of resistance during therapy limits its curative potential. The mechanisms identified in vitro include alterations in cellular drug transport, enhanced DNA repair and an enhanced intracellular detoxification system [6]. A promising way to circumvent CDDP resistance is the use of a resistance modulator [7], [8] or the development of non-cross-resistance agents [9].

In the present study, we examined and compared the antitumor effect of IH-901 with that of CDDP in four human cancer cell lines and one subline resistant to CDDP. The main focus of this study was to investigate the effect of IH-901 on acquired resistance to CDDP.

Section snippets

Chemicals

IH-901 was prepared by incubating ginseng saponins and intestinal bacteria as described [1]. The structure was confirmed by a series of spectrometric analyses and is shown in Fig. 1 (>99% purity, white powder). IH-901 and ginsenoside Rb1 were dissolved in dimethyl sulfoxide (DMSO) and diluted with culture medium to the desired concentrations. CDDP was obtained from United Pharmaceutics (Seoul, Korea) and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) was a product of Sigma

Results and discussion

Four human cancer cell lines known to be sensitive to CDDP and one subline showing resistance to CDDP were used in the present study. The origins of the solid tumor were lung (PC-14), liver (HepG2) and stomach (MKN45) and the human myeloid leukemia cell line was used as a cell line of hematopoietic origin. All of the cells grew in a suspension form while the HepG2 cells grew in an adherent form.

The growth inhibitory effects of IH-901 against four cancer cell lines are shown in Fig. 2 and the

Acknowledgements

This work was supported by a grant of the '98 Good Health R&D Project (HMP-96-D-5-1047), Ministry of Health and Welfare, Korea.

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