Abstract
Trichothecene macrolides comprise a class of valuable leading compounds in developing anticancer drugs, however, there are few reports concerning their anticancer mechanisms, especially the anticancer mechanism of the 10,13-cyclotrichothecane derivatives that are found mainly in symbiotic fungi. In vitro anticancer activity of two trichothecene macrolides mytoxin B and myrothecine A against the human hepatocarcinoma cell line SMMC-7721 was investigated in the present study. MTT assay showed that mytoxin B and myrothecine A inhibited the proliferation of SMMC-7721 cells in dose- and time-dependent manners. Annexin V-FITC/PI dual staining assay revealed that mytoxin B and myrothecine A both could induce SMMC-7721 cells apoptosis in a dose-dependent manner. The decreased expression level of anti-apoptotic protein Bcl-2 and the increased expression level of pro-apoptotic protein Bax were observed apparently in Western blot analysis. The reduced ratio of Bcl-2/Bax further confirmed the apoptosis-inducing effect of mytoxin B and myrothecine A on SMMC-7721 cells. Moreover, the expression levels of caspases-3, -8, and -9, and cleaved caspases-3, -8, and -9 were all upregulated in both mytoxin B and myrothecine A-treated cells in Western blot analysis, which indicated that both compounds might induce SMMC-7721 cells apoptosis through not only the death receptor pathway but also the mitochondrial pathway. Finally, mytoxin B and myrothecine A were found to reduce the activity of PI3K/Akt signaling pathway that was similar to the effect of LY294002 (a potent and specific PI3K inhibitor), suggesting that both mytoxin B and myrothecine A might induce SMMC-7721 cells apoptosis via PI3K/Akt pathway.
Highlights
Biotoxin is an important resource for developing new anticancer drugs and some biotoxins have been successfully used in clinical therapy, such as vincristine and camptothecin
In the present study, we focused on in the present study, we focused on the Bcl-2 protein family, caspases, and PI3K/Akt the Bcl-2pathway protein to family, caspases, and PI3K/Akt signaling pathway to investigate the induced signaling investigate the induced apoptosis mechanism of mytoxin apoptosis mechanism of mytoxin
Contains a 12,13-epoxy group in the sesquiterpene residue, while myrothecine A forms a 10,13-carbocycle through acid rearrangement of the 12,13-epoxy group
Summary
Biotoxin is an important resource for developing new anticancer drugs and some biotoxins have been successfully used in clinical therapy, such as vincristine and camptothecin. As one kind of of mycotoxin, trichothecene macrolides have attracted attention inin the the development development of mycotoxin, trichothecene macrolides have attracted a alotlotofofattention anticancer drugs. Trichothecene macrolides, structurally with an additional ring between anticancer drugs. Trichothecene macrolides, structurally with an additional ring between C-4C-4 andand CC-15 attached. 12,13-epoxy trichothecene skeleton, usually produced various species attached at at thethe. 12,13-epoxy trichothecene skeleton, areare usually produced by by various species of of Myrothecium.
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