Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Luszczek, Wioleta; Cheriyath, Venugopalan; Mekhail, Tarek; Borden, Ernest C.

doi:10.1158/1535-7163.mct-10-0309

Cited by 78 publications

(48 citation statements)

References 48 publications

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“…In contrast, recent studies suggest that IFNs and other inflammatory cytokines may augment tumor progression (de Visser et al, 2006;Calogero et al, 2007;DeNardo and Coussens, 2007;Bektas et al, 2008;DeNardo et al, 2008). ISG signatures that may be predictive of DNA damage resistance in bronchial and breast carcinomas have been described (Einav et al, 2005;Weichselbaum et al, 2008;Luszcek et al, 2010). Supporting the potential pro-tumor activity of some ISGs, we and others identified G1P3 (ISG 6-16, IFI6), a gene robustly stimulated by IFNs, as an antiapoptotic protein (Tahara et al, 2005;Cheriyath et al, 2007).…”

Section: Introductionsupporting

confidence: 52%

“…Contrary to evidence for IFNs as suppressive factors in cancer evolution, recent studies suggested that some of its target genes (ISGs) may contribute to the progression of malignancies (Tahara et al, 2005;Cheriyath et al, 2007;Bektas et al, 2008;Weichselbaum et al, 2008;Luszcek et al, 2010). However, the functional consequence of upregulated ISGs in cancer development and progression has not been well delineated (Sorbello et al, 2003;Bektas et al, 2008;Weichselbaum et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

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G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer

et al. 2011

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Hormonally regulated survival factors can have an important role in breast cancer. Here we elucidate G1P3, a survival protein induced by interferons (IFNs), as a target of estrogen signaling and a contributor to poor outcomes in estrogen receptor-positive (ER þ ) breast cancer. Compared with normal breast tissue, G1P3 was upregulated in the malignant epithelium (50 Â higher) and was induced by estrogen ex vivo. In accord with its overexpression in early stages of breast cancer (hyperplasia and ductal carcinoma in situ), in morphogenesis assays G1P3 enhanced the survival of MCF10A acinar luminal cells causing hyperplasia by suppressing detachmentinduced loss of mitochondrial potential and apoptosis (anoikis). In cells undergoing anoikis, G1P3 attenuated the induction of Bim protein, a proapoptotic member of the Bcl-2 family and reversed the downmodulation of Bcl-2 protein. Downregulation of G1P3 induced spontaneous apoptosis in BT-549 breast cancer cells and significantly reduced the growth of ER þ breast cancer cell MCF7 (Pp0.01), further suggesting its prosurvival activity. In agreement with its induction by estrogen, G1P3 antagonized tamoxifen, an inhibitor of ER in MCF7 cells. More importantly, elevated expression of G1P3 was significantly associated with decreased relapsefree and overall survival in ER þ breast cancer patients (Pp0.01). Our studies suggest that elevated expression of G1P3 may perturb canonical tumor-suppressing activity of IFNs partly by affecting the balance of pro-and antiapoptotic members of Bcl-2 family proteins, leading to breast cancer development and resistance to therapies.

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Section: Introductionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 97%

G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer

et al. 2011

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“…A combination of bromodeoxyuridine and distamycin A induced cellular senescence, activation of STAT1, and upregulation of ISGs (32). Luszczek and colleagues used a combination of DNA-methyltransferase I and histone deacetylase (HDAC) inhibitors (HDACi) to induce DNA damage in small cell lung cancer cell lines and found that resistant cell lines overexpressed STAT1 and ISGs (33). These results suggest that STAT1 overexpression is associated with resistance of tumor cells to antitumor drugs.…”

Section: Chemoresistance and The Stat1 Pathwaymentioning

confidence: 99%

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

Khodarev

Roizman²,

Weichselbaum³

2012

Clinical Cancer Research

158

167

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STAT1 is activated by IFNs and other cell signals. Following activation, STAT1 is translocated to the nuclei and activates transcription of IFN-stimulated genes. Although the activation of STAT1 by IFNs is classically associated with antiviral defense and tumor-suppressive functions, emerging data indicate that expression of the STAT1 pathway confers cellular resistance to DNA-damaging agents and mediates aggressive tumor growth. Recent advances in the development of Janus-activated kinase/Stat inhibitors and peptide inhibitors specific for individual Stat proteins may provide new insights into the controversial functions of this pathway. Clin Cancer Res; 18(11); 3015-21. Ó2012 AACR.

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“…32,33 Importantly, synergistic effects of HDACi and the DNMT inhibitor DAC were reported for growth inhibition, DNA damage, and apoptosis induction in different tumor entities. [34][35][36] Again, the underlying mechanism of action is not validated yet, but HDACi appear to decelerate removal of incorporated DAC from DNA, thereby enhancing the harmful action of DAC. 37 In the setting of the 2 major types of esophageal cancer, this study addressed the basic molecular effects (e.g.…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

Ahrens¹,

Timme

Hoeppner³

et al. 2015

Epigenetics

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Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.

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Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Cited by 78 publications

References 48 publications

G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer

G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

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