Regulation of Autophagy by Reactive Oxygen Species (ROS): Implications for Cancer Progression and Treatment

Azad, Meghan B.; Chen, Yongqiang; Gibson, Spencer B.

doi:10.1089/ars.2008.2270

Cited by 678 publications

(533 citation statements)

References 114 publications

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“…Therefore, inhibition of prosurvival members of the Bcl-2 family by BH3 mimetics, especially by pan-Bcl-2 inhibitors, might also hamper the antioxidative capacity of cells. Given the fact that oxidative stress is also known to stimulate autophagy in several experimental paradigms (53,54), it is presumably involved in the prominent induction of gossypol-dependent autophagy observed in our experiments. Indeed, (−)-gossypol was previously shown to be a potent inductor of oxidative stress in colorectal cancer cells (22).…”

Section: Discussionmentioning

confidence: 73%

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Voss

Senft

Lang

et al. 2010

Molecular Cancer Research

172

145

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Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2′, and ABT-737, whereas the pan-Bcl-2 inhibitor (−)-gossypol efficiently induced cell death. Furthermore, (−)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O 6 -methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (−)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (−)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1.

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Section: Discussionmentioning

confidence: 73%

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Voss

Senft

Lang

et al. 2010

Molecular Cancer Research

172

145

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“…More importantly, the inhibition of autophagy markedly enhanced the ROS level in 3,4,4'-THS-treated A549 cells. Autophagy can reportedly remove damaged mitochondria to limit ROS amplification [30] . The mitochondria pathway is a key signaling pathway in apoptosis induction (the intrinsic cell death pathway).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol analogue 3,4,4′-trihydroxy-trans-stilbene induces apoptosis and autophagy in human non-small-cell lung cancer cells in vitro

et al. 2015

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Aim:To investigate the effects of 3,4,4′-trihydroxy-trans-stilbene (3,4,4′-THS), an analogue of resveratrol, on human non-small-cell lung cancer (NSCLC) cells in vitro. Methods: Cell viability of NSCLC A549 cells was determined by MTT assay. Cell apoptosis was evaluated using flow cytometry and TUNEL assay. Cell necrosis was evaluated with LDH assay. The expression of apoptosis-or autophagy-associated proteins was measured using Western blotting. The formation of acidic compartments was detected using AO staining, neutral red staining and Lysotracker-Red staining. LC3 punctae were analyzed with fluorescence microscopy. Results: Treatment with 3,4,4′-THS (10-80 μmol/L) concentration-dependently inhibited the cell viability. It did not cause cell necrosis, but induced apoptosis accompanied by up-regulation of cleavaged PARP, caspase3/9 and Bax, and by down-regulation of Bcl-2 and surviving. It also increased the formation of acidic compartments, LC3-II accumulation and GFP-LC3 labeled autophagosomes in the cells. It inhibited the mTOR-dependent pathway, but did not impair autophagic flux. 3,4,4′-THS-induced cell death was enhanced by the autophagy inhibitors 3-MA (5 mmol/L) or Wortmannin (2 μmol/L). Moreover, 3,4,4′-THS treatment elevated the ROS levels in the cells, and co-treatment with 3-MA further elevated the ROS levels. 3,4,4′-THS-induced apoptosis and autophagy in the cells was attenuated by NAC (10 mmol/L) Conclusion: 3,4,4′-THS induces both apoptosis and autophagy in NSCLC A549 cells in vitro. Autophagy inhibitors promote 3,4,4′-THSinduced apoptosis of A549 cells, thus combination of 3,4,4′-THS and autophagy inhibitor provides a promising strategy for NSCLC treatment.

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“…In autophagy parts of the cytoplasm is sequestered into a double-membrane autophagosome and delivered to lysosomes for breakdown and recycling [31]. Azab et al (2009) revealed that 2ME2 induces autophagy in human glioblastoma-astrocytoma epithelial-like cell line (U87), human cervical adenocarcinoma cells (HeLa) and transformed human embryonic kidney cells (HEK293) [32].…”

Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol-bis-sulfamate induces apoptosis and autophagy in a tumorigenic breast epithelial cell line

Visagie

Joubert

2011

Mol Cell Biochem

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In anticancer research where the focus is on finding agents that induces cell death while leaving nontumorigenic cells less affected, a novel 2-methoxyestradiol derivative has come forth. 2-Methoxyestradiol-bissulphamate (2-MeOE2bisMATE) is a 2-methoxyestradiol derivative produced by bis-sulphamoylation which possesses increased antiproliferative activity and biological availability. Several questions remain regarding the the type of cell death mechanisms and possible induction of autophagy by 2-MeOE2bisMATE. The aim of this in vitro study was to investigate the cell death mechanisms exerted by 2-MeOE2bisMATE in an adenocarcinoma cell line (MCF-7) by analyzing its influence on cell growth, morphology and possible induction of cell death. Spectrophotometry (crystal violet staining), transmission electron microscopy (TEM), light microscopy (haematoxylin and eosin staining) and fluorescent microscopy (Hoechst 33342, propidium iodide and acridine orange) were employed. Spectrophotometrical studies indicated that 2-MeOE2bisMATE decreased cell numbers to 75% in MCF-7 cells after 24 h and to 47% after 48 h of exposure. TEM demonstrated membrane blebbing, nuclear fragmentation and chromatin condensation indicating hallmarks of apoptosis. Light microscopy revealed the presence of several cells blocked in metaphase and apoptotic cells were also observed.Fluorescent microscopy demonstrated increased lysosomal staining; suggesting the induction of autophagy. 2-MeOE2bisMATE shows therapeutic potential as an anticancer agent and the investigation of the cell death mechanisms used by 2-MeOE2bisMATE thus warrants further investigation.

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Regulation of Autophagy by Reactive Oxygen Species (ROS): Implications for Cancer Progression and Treatment

Cited by 678 publications

References 114 publications

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Resveratrol analogue 3,4,4′-trihydroxy-trans-stilbene induces apoptosis and autophagy in human non-small-cell lung cancer cells in vitro

2-Methoxyestradiol-bis-sulfamate induces apoptosis and autophagy in a tumorigenic breast epithelial cell line

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