In Benign Barrett's Epithelial Cells, Acid Exposure Generates Reactive Oxygen Species That Cause DNA Double-Strand Breaks

Zhang, Hui Ying; Hormi–Carver, Kathy; Zhang, Xi; Spechler, Stuart J.; Souza, Rhonda F.

doi:10.1158/0008-5472.can-09-2518

Cited by 94 publications

(78 citation statements)

References 40 publications

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“…5E and F). We further observed increased H2AX phosphorylation, which is a hallmark of ongoing DNA damage as a result of increased ROS (44,45). The response of APL cells to MC2392 includes the generation of ROS as a consequence of Bid cleavage, which triggers mitochondrial membrane permeabilization.…”

Section: Mc2392-induced Cell Death Involves Ros and Caspase-8mentioning

confidence: 83%

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

et al. 2014

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HDAC inhibitors (HDACi) are widely used in the clinic to sensitize tumorigenic cells for treatment with other anticancer compounds. The major drawback of HDACi is the broad inhibition of the plethora of HDAC-containing complexes. In acute promyelocytic leukemia (APL), repression by the PML-RARa oncofusion protein is mediated by an HDAC-containing complex that can be dissociated by pharmacologic doses of all trans retinoic acid (ATRA) inducing differentiation and cell death at the expense of side effects and recurrence. We hypothesized that the context-specific close physical proximity of a retinoid and HDACi-binding protein in the repressive PML-RARa-HDAC complex may permit selective targeting by a hybrid molecule of ATRA with a 2-aminoanilide tail of the HDAC inhibitor MS-275, yielding MC2392. We show that MC2392 elicits weak ATRA and essentially no HDACi activity in vitro or in vivo. Genome-wide epigenetic analyses revealed that in NB4 cells expressing PML-RARa, MC2392 induces changes in H3 acetylation at a small subset of PML-RARa-binding sites. RNA-seq reveals that MC2392 alters expression of a number of stress-responsive and apoptotic genes. Concordantly, MC2392 induced rapid and massive, caspase-8-dependent cell death accompanied by RIP1 induction and ROS production. Solid and leukemic tumors are not affected by MC2392, but expression of PML-RARa conveys efficient MC2392-induced cell death. Our data suggest a model in which MC2392 binds to the RARa moiety and selectively inhibits the HDACs resident in the repressive complex responsible for the transcriptional impairment in APLs. Our findings provide proof-of-principle of the concept of a context-dependent targeted therapy. Cancer Res; 74(8); 2328-39. Ó2014 AACR.

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Section: Mc2392-induced Cell Death Involves Ros and Caspase-8mentioning

confidence: 83%

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

et al. 2014

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“…The gastroesophageal reflux of acid is thought to contribute to the development of this lethal tumor (36), but the incidence of esophageal adenocarcinoma continues to rise at an alarming rate, despite the widespread use of potent acid-suppressive medications, such as proton pump inhibitors (PPIs), for the treatment of GERD (25). This suggests that refluxed hydrochloric acid might not be the sole factor contributing to esophageal carcinogenesis in GERD.…”

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confidence: 99%

Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett's epithelial cells

Huo

Juergens

Zhang

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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117

120

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Gastroesophageal reflux is associated with adenocarcinoma in Barrett's esophagus, but the incidence of this tumor is rising, despite widespread use of acid-suppressing medications. This suggests that refluxed material other than acid might contribute to carcinogenesis. We looked for potentially carcinogenetic effects of two bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on Barrett's epithelial cells in vitro and in vivo. We exposed Barrett's (BAR-T) cells to DCA or UDCA and studied the generation of reactive oxygen/nitrogen species (ROS/RNS); expression of phosphorylated H2AX (a marker of DNA damage), phosphorylated IkBα, and phosphorylated p65 (activated NF-κB pathway proteins); and apoptosis. During endoscopy in patients, we took biopsy specimens of Barrett's mucosa before and after esophageal perfusion with DCA or UDCA and assessed DNA damage and NF-κB activation. Exposure to DCA, but not UDCA, resulted in ROS/RNS production, DNA damage, and NF-κB activation but did not increase the rate of apoptosis in BAR-T cells. Pretreatment with N-acetyl-l-cysteine (a ROS scavenger) prevented DNA damage after DCA exposure, and DCA did induce apoptosis in cells treated with NF-κB inhibitors (BAY 11-7085 or AdIκB superrepressor). DNA damage and NF-κB activation were detected in biopsy specimens of Barrett's mucosa taken after esophageal perfusion with DCA, but not UDCA. These data show that, in Barrett's epithelial cells, DCA induces ROS/RNS production, which causes genotoxic injury, and simultaneously induces activation of the NF-κB pathway, which enables cells with DNA damage to resist apoptosis. We have demonstrated molecular mechanisms whereby bile reflux might contribute to carcinogenesis in Barrett's esophagus.

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“…An enhanced lipid peroxidation during tissue acidosis has been previously reported (6,31,47). Therefore, extracellular TME acidosis may potentiate enhanced oxidative stress and oxidizing damage (73).…”

Section: Role Of Tme In Ros Generationmentioning

confidence: 88%

Janus-Faced Tumor Microenvironment and Redox

Khramtsov

Gillies

2014

Antioxidants & Redox Signaling

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Significance: Tumor microenvironment (TME) is a complex term that includes extracellular matrix, blood vessels, endothelial, stromal, and inflammatory cells, and other supporting structures of the particular organ; and physiological components such as oxygen, pH, nutrients, waste products, signaling molecules, reducing/oxidizing species, growth factors, protumorigenic factors, etc. TME is now widely recognized as a major contributor to cancer aggression and treatment resistance and as a potential target for therapeutic intervention. Recent Advances: Among important physiological parameters of the TME, tissue hypoxia is considered to be a consequence of imbalanced angiogenesis and is associated with changes in metabolic pathways, including a higher dependence on glycolysis resulting in tissue acidosis. Both hypoxia and acidosis affect the tissue redox status and its key intracellular component, glutathione (GSH). Numerous publications support that these local TME conditions select for outgrowth of cells with appropriate phenotypes, which can reflect underlying genetics. Critical Issues: Here, we hypothesize that specific patterns of local TME, namely, tumor oxygenation, extracellular pH, redox, and GSH homeostasis, acting in orchestrated mechanism, can promote cancer cell survival, while at the same time being highly toxic and mutagenic for normal cells, thus contributing to the growth of cancers at the expense of the normal tissues they are invading. This review summarizes the experimental observations that support the hypothesized Janus-faced character of the redox axis. Future Directions: Normalizing the TME redox parameters may decrease the selection pressure for malignant phenotypes, therefore providing a tool for TME-targeted anticancer therapy. Antioxid. Redox Signal. 21, 723-729.

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In Benign Barrett's Epithelial Cells, Acid Exposure Generates Reactive Oxygen Species That Cause DNA Double-Strand Breaks

Cited by 94 publications

References 40 publications

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett's epithelial cells

Janus-Faced Tumor Microenvironment and Redox

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