Anti-tumor effect of Demethoxyfumitremorgin C, isolated from Marine Fungus Aspergillus fumigatus, through caspase-dependent pathway on Human Prostate cancer PC3 cell line

Abstract

Human prostate cancer is second cause of male death every year in the western countries. Prostate cancer incidence rate is increased in eastern countries such as Japan, Singapore and Korea. Recently, much attention has been paid on chemotherapeutic compounds from natural product as anti-cancer agents. In the present study, marine-derived fungus Aspergillus fumigatus was cultivated and isolated three secondary me-tabolites (Cyclotryprostatin A (C1), Tryprostatin B (C2), and Demethoxy-fumitremorgin (C3)) from marine fungus strain-150 (MFS-150) culture broth extract. The structures of compounds were elucidated via Low resolution electron ionization mass spectrometer (LREIMS), 1D, and 2D nuclear magnetic resonance (NMR) spec-tra. To investigate the effect of secondary metabolites in inhibition of cell prolifera-tion and induction apoptosis on prostate cancer cells, PC3 cells were treated with dif-ferent concentrations (25, 50, 100 μM) and various time intervals (24, 48, 72h) of Cy-clotryprostatin A (C1), Tryprostatin B (C2), and Demethoxyfumitremorgin (C3). Among them, Demethoxyfumitremorgin (C3) compound has shown anti-proliferative effect on PC3 cells whereas other compounds did not shows significant cytotoxicity. Furthermore, we tested the cell proliferation and apoptosis activity of Demethoxy-fumitremorgin C (C3) in PC3 cells and results shows that significant inhibition on cell proliferation in dose and time dependent manner. The level of cell cycle arrest relative protein expression, phospho-cdc2, cyclin A, D, E, CDK 2, and 4 were decreased by Demethoxyfumitremorgin C (C3) in a dose-dependent manner. In addition, Demeth-oxyfumitremorgin C (C3) regulated the anti- and pro-apoptotic proteins like Bcl-2, Bcl-xL and Bax. Also, relative proteins for apoptosis, cleaved PARP, p-p53, p-p21, caspase-3, -8, and -9 were increased by Demethoxyfumitremorgin C (C3). Taken to-gether, these results implicated that Demethoxyfumitremorgin C (C3) has anti-cancer effect on prostate cancer PC3 cells via suppress cell proliferation through cell cycle arrest at G1 phase and induction of apoptosis via regulating pro- and anti-apoptotic protein expressions in caspase-dependent pathway. Thus, Demethoxyfumitremorgin C (C3) could be used for therapeutic agent for treatment of prostate cancer.