Colossolactone H, a new Ganoderma triterpenoid exhibits cytotoxicity and potentiates drug efficacy of gefitinib in lung cancer

• Published in: Fitoterapia Vol. 114; pp. 81 - 91
• Main Authors: Chen, Su-Yu, Chang, Chao-Lin, Chen, Teng-Hai, Chang, Ya-Wen, Lin, Shwu-Bin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2016
• Subjects: Animals; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; cell cycle; cell growth; Cell Line, Tumor; Colossolactone; Complementary medicine; Cytotoxicity; DNA Damage; Down-Regulation; drugs; fruiting bodies; Ganoderma; Ganoderma - chemistry; Ganoderma colossum; gene expression regulation; genes; growth retardation; Humans; Lung Neoplasms; Male; medicinal fungi; medicinal plants; Mice; Mice, Inbred BALB C; Molecular Structure; neoplasm cells; oxidation; Oxidative damage; Quinazolines - pharmacokinetics; reactive oxygen species; Reactive Oxygen Species - metabolism; therapeutics; Triterpene dilactone; Triterpenes - isolation & purification; Triterpenes - pharmacology; triterpenoids; tumor suppressor protein p53; Tumor Suppressor Protein p53 - metabolism; Up-Regulation; Xenograft Model Antitumor Assays; Colossolactone G (PubChem CID: 10187119); Oxidative damage; Colossolactone; Ganoderma colossum; GO; Glutathione (PubChem CID: 124886); colo H; Cytotoxicity; Complementary medicine; Triterpene dilactone; ROS; Gefitinib (PubChem CID: 123631); GSH
• DOI: 10.1016/j.fitote.2016.08.015
• ISSN: 0367-326X

Three pentacyclic triterpene dilactones were isolated from the fruiting bodies of Ganoderma colossum, a medicinal mushroom. Colossolactone H (colo H) as a new compound and the most cytotoxic among the isolates was studied for its anticancer mechanism and the potential use in cancer therapy. Gene expression profiling analysis indicated that treatment of lung cancer cells with colo H caused upregulation of 252 genes and downregulation of 398 genes. Gene ontology enrichment analysis indicated that the downregulated genes were the most significantly enriched in cell cycle progression, and the upregulated genes were significantly enriched in metabolic process, cellular response to stimulus, and oxidation reduction. Accordingly, colo H was found to halt cell growth and induce cell apoptosis via the elevation of cellular reactive oxygen species to cause DNA damage and the increase of tumor suppressor p53 protein. These events facilitate additive cytotoxicity of colo H and gefitinib for gefitinib-resistant H1650 lung cancer cells. Furthermore, combination of colo H and gefitinib effectively inhibited the growth of tumor xenografts in athymic mice. In addition to the efficacy in adjunctive cancer therapy, we have also demonstrated the isolation of colo H from cultivated G. colossum. Thus it is feasible to use colo H or Ganoderma colossum for cancer therapy. [Display omitted]