Ganoderic acid X, a lanostanoid triterpene, inhibits topoisomerases and induces apoptosis of cancer cells

• Published in: Life sciences (1973) 2005-06, Vol.77 (3), p.252-265
• Main Authors: Li, Chyi-Hann, Chen, Pei-Yu, Chang, Ue-Min, Kan, Lou-Sing, Fang, Woei-Horng, Tsai, Keh-Sung, Lin, Shwu-Bin
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - metabolism; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Apoptosis; Apoptosis - physiology; Caspase 3; Caspases - metabolism; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Ganoderic acid X; Ganoderma - chemistry; Ganoderma triterpene; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Lanosterol - analogs & derivatives; Lanosterol - chemistry; Lanosterol - metabolism; Lanosterol - therapeutic use; Medicine, Chinese Traditional; Molecular Structure; Neoplasms - drug therapy; Neoplasms - metabolism; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Topoisomerase inhibitor; Triterpenes - chemistry; Triterpenes - metabolism; Triterpenes - therapeutic use
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2004.09.045

Lanostanoid triterpenes isolated from Ganoderma amboinense were found to inhibit the growth of numerous cancer cell lines, and some of them inhibited the activities of topoisomerases I and IIα in vitro. Among the bioactive isolates, one of the most potent triterpene was identified to be 3α-hydroxy-15α-acetoxy-lanosta-7,9(11),24-trien-26-oic acid, ganoderic acid X (GAX). Treatment of human hepatoma HuH-7 cells with GAX caused immediate inhibition of DNA synthesis as well as activation of ERK and JNK mitogen-activated protein kinases, and cell apoptosis. Molecular events of apoptosis including degradation of chromosomal DNA, decrease in the level of Bcl-xL, the disruption of mitochondrial membrane, cytosolic release of cytochrome c and activation of caspase-3 were elucidated. The ability of GAX to inhibit topoisomerases and to sensitize the cancer cells toward apoptosis fulfills the feature of a potential anticancer drug.