Apoptosis-inducing effect of diketopiperazine disulfides produced by Aspergillus sp. KMD 901 isolated from marine sediment on HCT116 colon cancer cell lines

Title
Apoptosis-inducing effect of diketopiperazine disulfides produced by Aspergillus sp. KMD 901 isolated from marine sediment on HCT116 colon cancer cell lines
Authors
최은주박진수김영주정지희이재균권학철양현옥
Keywords
marine derived fungus; marine sediment; Aspergillus; secondary metabolite; antitumour; apoptosis; colon cancer cell lines; diketopiperazine disulfides; Aspergillus sp. KMD 901
Issue Date
2011-01
Publisher
Journal of applied microbiology
Citation
VOL 110, NO 1, 304-313
Abstract
Aims: Research is to identify the bioactive secondary metabolites produced by Aspergillus sp. KMD 901 isolated from marine sediment and to assess their apoptosis-inducing effects. Methods and Results: Aspergillus sp. KMD 901 was isolated from marine sedi- ment obtained from the East Sea of Korea. An ethyl acetate extract of KMD 901 exhibited potent cytotoxic activity towards five cancer cell lines (HCT116, AGS, A549, MCF-7 and HepG2). Sequencing of the internal transcribed spacer (ITS) region in this strain allowed us to identify KMD 901 as a strain of Aspergillus versicolor. The cytotoxic compounds from Aspergillus sp. KMD 901 were purified by reversed-phase high-performance liquid chromatography and identified as diketopiperazine disulfides through spectroscopic analyses includ- ing extensive 2D NMR and mass spectrometry. The diketopiperazine disulfides were found to induce apoptosis in HCT116 cells based on cell morphology, DNA fragmentation observed by agarose gel electrophoresis, Annexin-V ⁄ PI staining using a flow cytometer and cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3, caspase-8, caspase-9 and Bcl-2 family proteins (Bcl-2, Bcl- xL and Bax) using Western blotting analysis. Further study using an in vivo xenograft model showed inhibitory effects of acetylapoaranotin (2) on tumour proliferation. Conclusion: A new diketopiperazine disulfide, deoxyapoaranotin (3), along with previously described acetylaranotin (1) and acetylapoaranotin (2) was sep- arated from Aspergillus sp. KMD 901 and found to have direct cytotoxic and apoptosis-inducing effects towards HCT116 colon cancer cell lines. Significance and Impact of the Study: These results suggest that the diketopip- erazine disulfides produced from Aspergillus sp., KMD 901, could be candidates for the development of apoptosis-inducing antitumour agents.
URI
http://pubs.kist.re.kr/handle/201004/38429
ISSN
1364-5072
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