Cancer Letters

Cancer Letters

Volume 246, Issues 1–2, 8 February 2007, Pages 210-217
Cancer Letters

Enhanced induction of mitochondrial damage and apoptosis in human leukemia HL-60 cells by the Ganoderma lucidum and Duchesnea chrysantha extracts

https://doi.org/10.1016/j.canlet.2006.02.014Get rights and content

Abstract

Combined treatment with the medicinal mushroom Ganoderma lucidum and the herb Duchesnea chrysantha extracts (GDE) causes a synergistic induction of mitochondrial damage and apoptosis in HL-60 cells. GDE treatment is selectively toxic to HL-60 leukemia cells whereas no cytotoxic effect is observed in normal peripheral blood mononuclear cells. GDE-induced apoptosis is associated with Bcl-2 down-regulation, Bax translocation, mitochondrial cytochrome c release and caspase-3 activation, suggesting that apoptosis by this combination occurs through the mitochondria-dependent pathway. The present findings suggest that this combination merits further investigation as a potential therapeutic agent for the treatment of cancer.

Introduction

Apoptosis is a major form of cell death and one relevant mechanism for radiation- and/or chemotherapy-induced cell death in human hematologic malignancies. An increase of the apoptotic threshold in lymphoma and leukemia is a relevant mechanism for treatment resistance [1]. Treatment strategies that specifically increase apoptotic cell death in malignancies and/or decrease apoptosis in normal tissue should be exploited in translational and clinical oncology research. In this study, we focus on the relevance of the use of medicinal hubs as an additional therapeutic intervention for a successful cancer therapy.

The medicinal mushroom Ganoderma lucidum and the herb Duchesnea chrysantha have been used traditionally in East Asia for the prevention and treatment of various diseases, including cancer. Their antioxidative, anti-inflammatory and immune enhancing properties, along with no toxicity, raise the possibilities that they could be effective in preventing cancer or related diseases. G. lucidum, which belongs to the Polyporaeae family, is currently being used as a dietary supplement in the form of spores, fruiting body or mushroom extract. This mushroom contains a large variety of biologically active polysaccharides and triterpenes with anti-tumor activities [2]. Of particular interest is the fact that Ganoderma is a rich source of bitter triterpenes. Indeed, about 100 different triterpenoids, which have a lanostane skeleton, were found in the fruiting bodies and mycelia of G. lucidum [3], [4]. Recent studies have shown that G. lucidum induces apoptosis, inhibits cell proliferation, and suppresses cell migration of highly invasive human breast and prostate cancer cells [5], [6]. D. chrysantha, which belongs to the Rosacae family, is a perennial plant and has traditionally been used to treat several kinds of illnesses such as congenital fever, toothache, and cancers in Korea, and its water extracts are edible and non-toxic. Phenolic compounds of D. chrysantha exert cytotoxic activities in human cancer cells [7]. The majority of the compounds isolated from Duchesnea are biologically active lectin and polysaccharides with antioxidative [8] and immunostimulatory properties (G.J. Jeong, unpublished observations), which contribute to their anticancer effects. However, the molecular mechanism responsible for the antitumor effects of Duchesnea has not been fully elucidated.

In the present study, we investigated a possible enhancing effect of G. lucidum plus D. chrysantha extracts on apoptosis and growth inhibition in human leukemia HL-60 cells, as these extracts contain biologically active compounds mainly responsible for anti-tumor activities. Here we show for the first time that combined treatment with Ganoderma extract and Duchesnea extract causes a synergistic induction of apoptosis as well as mitochondrial damage. The present findings suggest that this combination merits further investigation as a potential therapeutic agent for the treatment of cancer.

Section snippets

Preparation of Duchesnea and Ganoderma extracts

The extracts of D. chrysantha and G. lucidum were isolated and characterized using the method described by Kim et al. [8] and Zhu et al. [9], respectively. Briefly, after extraction of the whole parts from D. chrysantha with boiling water, the aqueous solution was extracted with an equal volume of chloroform and then evaporated to remove chloroform. The water-soluble polysaccharide-enriched fraction was isolated by precipitation with ethanol from the concentrated extract in two steps. After

Induction of apoptosis and growth inhibition in GDE-treated HL-60 cells

Using a conventional tetrazolium-based colorimetric cell proliferation assay, we evaluated the cytotoxicity of Duchesnea extract or Ganoderma extract on HL-60 cells. After a 48 h incubation, the concentrations of Duchesnea and Ganoderma extracts required to kill 50% (IC50) of the cells were 160 and 210 μg/ml, respectively. Duchesnea extract was slightly more cytotoxic than Ganoderma extract.

To establish the long-term proliferation effects of each extract, we performed a clonogenic assay, in which

Discussion

Here we report for the first time that combined treatment with the G. lucidum and D. chrysantha extract causes a synergistic induction of mitochondrial damage and apoptosis in human leukemia HL-60 cells. Recently, mitochondria have been proposed as a novel prospective target for chemotherapy-induced apoptosis [20]. Several chemotherapeutic agents can cause, directly or indirectly, apoptosis by insult to the mitochondria. The interaction of anticancer agents with mitochondria results in an

Acknowledgements

This Work was funded by Nuclear R&D program of the Ministry of Science and Technology of the Republic of Korea.

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