RRC ID 61241
Author Shimizu T, Kawai J, Ouchi K, Kikuchi H, Osima Y, Hidemi R.
Title Agarol, an ergosterol derivative from Agaricus blazei, induces caspase-independent apoptosis in human cancer cells.
Journal Int J Oncol
Abstract Agaricus blazei (A. blazei) is a mushroom with many biological effects and active ingredients. We purified a tumoricidal substance from A. blazei, an ergosterol derivative, and named it 'Agarol'. Cytotoxic effects of Agarol were determined by the MTT assay using A549, MKN45, HSC-3, and HSC-4 human carcinoma cell lines treated with Agarol. Apoptosis was detected by flow cytometry analysis. Reactive oxygen species (ROS) levels and mitochondria membrane potential (∆ψm) were also determined by flow cytometry. Western blot analysis was used to quantify the expression of apoptosis-related proteins. Agarol predominantly induced apoptosis in two p53-wild cell lines (A549 and MKN45) compared to the other p53-mutant cell lines (HSC-3 and HSC-4). Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of ROS, reduced ∆ψm, release of apoptosis-inducing factor (AIF) from the mitochondria to the cytosol, upregulation of Bax, and downregulation of Bcl-2. Caspase-3 activities did not increase, and z-VAD-fmk, a caspase inhibitor, did not inhibit the Agarol-induced apoptosis. These findings indicate that Agarol induces caspase-independent apoptosis in human carcinoma cells through a mitochondrial pathway. The in vivo anticancer activity of Agarol was confirmed in a xenograft murine model. This study suggests a molecular mechanism by which Agarol induces apoptosis in human carcinoma cells and indicates the potential use of Agarol as an anticancer agent.
Volume 48(4)
Pages 1670-8
Published 2016-4-1
DOI 10.3892/ijo.2016.3391
PMID 26893131
MeSH Agaricus / chemistry* Animals Antineoplastic Agents / administration & dosage* Antineoplastic Agents / pharmacology Apoptosis Caspases / metabolism Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Ergosterol / administration & dosage* Ergosterol / pharmacology Gene Expression Regulation, Neoplastic / drug effects Humans Membrane Potential, Mitochondrial / drug effects* Mice Neoplasms / drug therapy* Neoplasms / metabolism Reactive Oxygen Species / metabolism* Signal Transduction / drug effects Xenograft Model Antitumor Assays
IF 3.571
Human and Animal Cells HSC-4(RCB1902) HSC-3(RCB1975)