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G226, a novel epipolythiodioxopiperazine derivative, induces autophagy and caspase-dependent apoptosis in human breast cancer cells in vitro.

He PX, Che YS, He QJ, Chen Y, Ding J - Acta Pharmacol. Sin. (2014)

Bottom Line: G226 also induced mitochondrial outer membrane permeabilization, resulted in the caspase-9 activation.Silencing of p62 or LC3 partially diminished caspase-8 and subsequent caspase-3 activation.LC3 silencing partially reversed G226-induced apoptosis, but p62 silencing elicited a subtle effect on G226-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

ABSTRACT

Aim: To investigate the effects of G226, a novel epipolythiodioxopiperazine derivative, on human breast cancer cells in vitro, and to explore its anticancer mechanisms.

Methods: A panel of human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, ZR-75-30, BT474, BT549, SK-BR-3, T47D and HBL100) was examined. Cell proliferation was measured using sulforhodamine B assay, and cell apoptosis was detected with flow cytometry and caspase activity assay. Western blotting, immunofluorescence and targeted gene knockdowns were used to study autophagy in the cells.

Results: G226 suppressed proliferation of the 9 breast cancer cell lines with a mean IC50 value of 48.5 nmol/L (the mean IC50 value of adriamycin, a reference compound, was 170.6 nmol/L). G226 induced dose-dependent apoptosis of MDA-MB-231 and MCF-7 cells, accompanied by markedly increased activities of caspase-8 and caspase-3/7, which were abolished by caspase inhibitors zVAD or zIETD. G226 also induced mitochondrial outer membrane permeabilization, resulted in the caspase-9 activation. Moreover, G226 dose-dependently enhanced the autophagy marker LC3-II and autophagy substrate p62 accumulation in the cells, which were co-localized with caspase-8. Silencing of p62 or LC3 partially diminished caspase-8 and subsequent caspase-3 activation. LC3 silencing partially reversed G226-induced apoptosis, but p62 silencing elicited a subtle effect on G226-induced apoptosis.

Conclusion: The novel epipolythiodioxopiperazine derivative G226 exerts potent anticancer action against human breast cancer cells in vitro, via triggering autophagy and caspase-dependent apoptosis.

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Cytotoxicity of G226 against human breast tumor cells. (A) Chemical structure of G226. (B) G226 inhibits human breast tumor cell proliferation in vitro.
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fig1: Cytotoxicity of G226 against human breast tumor cells. (A) Chemical structure of G226. (B) G226 inhibits human breast tumor cell proliferation in vitro.

Mentions: Natural products are rich sources of chemically diverse, potential therapeutic leads and have attracted tremendous interest due to their potential for considerable yields of new anti-tumor chemical entities. In this work, we aimed to identify potential anti-cancer drug candidates in natural products. Epipolythiodioxopiperazines (ETPs) are synthesized by fungi, and recent studies have highlighted the potential of ETPs as anticancer agents1. According to our previous studies, we found that 11,11′-dideoxyverticillin, an ETP, which is isolated from Shiraia bambusicola, exhibits potent cytotoxicity against a broad spectrum of cancer cell lines in vitro2. In this current study, we report that G226 (Figure 1A), a novel 11′-deoxyverticillin A derivative, exhibits potent cytotoxic activity against breast cancer. We also determine the mechanism by which G226 kills cancer cells and find that it significantly induces apoptosis and autophagy in breast cancer cells.


G226, a novel epipolythiodioxopiperazine derivative, induces autophagy and caspase-dependent apoptosis in human breast cancer cells in vitro.

He PX, Che YS, He QJ, Chen Y, Ding J - Acta Pharmacol. Sin. (2014)

Cytotoxicity of G226 against human breast tumor cells. (A) Chemical structure of G226. (B) G226 inhibits human breast tumor cell proliferation in vitro.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4125716&req=5

fig1: Cytotoxicity of G226 against human breast tumor cells. (A) Chemical structure of G226. (B) G226 inhibits human breast tumor cell proliferation in vitro.
Mentions: Natural products are rich sources of chemically diverse, potential therapeutic leads and have attracted tremendous interest due to their potential for considerable yields of new anti-tumor chemical entities. In this work, we aimed to identify potential anti-cancer drug candidates in natural products. Epipolythiodioxopiperazines (ETPs) are synthesized by fungi, and recent studies have highlighted the potential of ETPs as anticancer agents1. According to our previous studies, we found that 11,11′-dideoxyverticillin, an ETP, which is isolated from Shiraia bambusicola, exhibits potent cytotoxicity against a broad spectrum of cancer cell lines in vitro2. In this current study, we report that G226 (Figure 1A), a novel 11′-deoxyverticillin A derivative, exhibits potent cytotoxic activity against breast cancer. We also determine the mechanism by which G226 kills cancer cells and find that it significantly induces apoptosis and autophagy in breast cancer cells.

Bottom Line: G226 also induced mitochondrial outer membrane permeabilization, resulted in the caspase-9 activation.Silencing of p62 or LC3 partially diminished caspase-8 and subsequent caspase-3 activation.LC3 silencing partially reversed G226-induced apoptosis, but p62 silencing elicited a subtle effect on G226-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

ABSTRACT

Aim: To investigate the effects of G226, a novel epipolythiodioxopiperazine derivative, on human breast cancer cells in vitro, and to explore its anticancer mechanisms.

Methods: A panel of human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, ZR-75-30, BT474, BT549, SK-BR-3, T47D and HBL100) was examined. Cell proliferation was measured using sulforhodamine B assay, and cell apoptosis was detected with flow cytometry and caspase activity assay. Western blotting, immunofluorescence and targeted gene knockdowns were used to study autophagy in the cells.

Results: G226 suppressed proliferation of the 9 breast cancer cell lines with a mean IC50 value of 48.5 nmol/L (the mean IC50 value of adriamycin, a reference compound, was 170.6 nmol/L). G226 induced dose-dependent apoptosis of MDA-MB-231 and MCF-7 cells, accompanied by markedly increased activities of caspase-8 and caspase-3/7, which were abolished by caspase inhibitors zVAD or zIETD. G226 also induced mitochondrial outer membrane permeabilization, resulted in the caspase-9 activation. Moreover, G226 dose-dependently enhanced the autophagy marker LC3-II and autophagy substrate p62 accumulation in the cells, which were co-localized with caspase-8. Silencing of p62 or LC3 partially diminished caspase-8 and subsequent caspase-3 activation. LC3 silencing partially reversed G226-induced apoptosis, but p62 silencing elicited a subtle effect on G226-induced apoptosis.

Conclusion: The novel epipolythiodioxopiperazine derivative G226 exerts potent anticancer action against human breast cancer cells in vitro, via triggering autophagy and caspase-dependent apoptosis.

Show MeSH
Related in: MedlinePlus