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