The Octyl Ester of Ginsenoside Rh2 Induces Lysosomal Membrane Permeabilization via Bax Translocation.

Fang Chen,Han Peng,Ze-Yuan Deng,Yong Sun,Zeng-Xing Xiong,Bing Zhang,Jiang-Ning Hu

doi:10.3390/nu8050244

Fang Chen, Han Peng + Show 5 more

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https://doi.org/10.3390/nu8050244

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Abstract

Ginsenoside Rh2 is a potential pharmacologically active metabolite of ginseng. Previously, we have reported that an octyl ester derivative of ginsenoside Rh2 (Rh2-O), has been confirmed to possess higher bioavailability and anticancer effect than Rh2 in vitro. In order to better assess the possibility that Rh2-O could be used as an anticancer compound, the underlying mechanism was investigated in this study. The present results revealed that lysosomal destabilization was involved in the early stage of cell apoptosis in HepG2 cells induced by Rh2-O. Rh2-O could induce an early lysosomal membrane permeabilization with the release of lysosomal protease cathepsins to the cytosol in HepG2 cells. The Cat B inhibitor (leu) and Cat D inhibitor (pepA) inhibited Rh2-O-induced HepG2 apoptosis as well as tBid production and Δφm depolarization, indicating that lysosomal permeabilization occurred upstream of mitochondrial dysfunction. In addition, Rh2-O induced a significant increase in the protein levels of DRAM1 and Bax (p < 0.05) in lysosomes of HepG2 cells. Knockdown of Bax partially inhibited Rh2-O-induced Cat D release from lysosomes. Thus it was concluded that Rh2-O induced apoptosis of HepG2 cells through activation of the lysosomal-mitochondrial apoptotic pathway involving the translocation of Bax to the lysosome.

Highlights

Ginsenoside Rh2, one of the major effective metabolites of ginseng, has been reported to suppress growth in various cancer cell lines [1,2,3]
The aim of this study was to determine whether lysosomal membrane permeabilization is involved in Rh2-O-induced HepG2 cell apoptosis, or if the release of cathepsins as the upstream signaling process could lead to mitochondrial dysfunction
The results provided first evidence that Rh2-O-treated HepG2 cells underwent lysosomal membrane permeabilization, suggesting that lysosomal destabilization occurred in the apoptosis cascade induced by Rh2-O

Summary

Introduction

Ginsenoside Rh2, one of the major effective metabolites of ginseng, has been reported to suppress growth in various cancer cell lines [1,2,3]. Rh2 has limited application in medical supplies due to its low oral bioavailability as well as high toxicity to normal cells [4,5]. (2014) found that Rh2-O possessed a better absorption than Rh2 in the Caco-2 system, and the transport mechanisms for both Rh2 and Rh2-O were transcellular passive diffusion [8]. The findings suggested that Rh2-O induced caspase-dependent apoptosis via the intrinsic pathway. These studies have confirmed that Rh2-O may be more efficient than Rh2 in anticancer activity.

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