Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer

Chu, Benjamin F.; Karpenko, Matthew; Liu, Z.; Aimiuwu, Josephine; Villalona‐Calero, Miguel A.; Chan, Kenneth K.; Grever, Michael R.; Otterson, Gregory A.

doi:10.1007/s00280-012-1986-8

Cited by 78 publications

(61 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One solution was to combine multiple drugs that act synergistically. A number of ongoing clinical trials are investigating the effects of combined therapy against different types of cancer (25)(26)(27). In our experimental system, the effect of combined treatment with SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis.…”

Section: Discussionmentioning

confidence: 80%

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

et al. 2015

View full text Add to dashboard Cite

Abstract. Studies on stem cell differentiation led to the identification of paused genes, characterized by the contemporary presence of both activator and repressor epigenetic markers (bivalent marking). TXNIP is an oncosuppressor gene the expression of which was reduced in breast cancer. In the present study, we evaluated whether the concept of epigenetic bivalent marking can be applied to TXNIP gene in breast cancer cells. Using chromatin immunoprecipitation (ChIP), three histone modifications were investigated: two associated with transcriptional activation, lysines 9-14 acetylation of H3 histone (H3K9K14ac) and lysine 4 trimethylation of H3 histone (H3K4me3), and one associated with transcriptional silencing, lysine 27 trimethylation of H3 histone (H3K27me3). According to the bivalent marking model, TXNIP gene appears to be paused in MDA157 cells (markers of active and repressed transcription are present), but are definitively silenced in MDA468 cells (presence of only markers of transcription repression). This was proven by evaluating TXNIP mRNA and protein levels after the treatment of cell lines with a histone deacetylase inhibitor (SAHA) and a poly-ADPribose polymerases inhibitor (PJ34). In MDA157 cells, SAHA and PJ34 showed a synergistic effect: a large increment was observed in TXNIP mRNA and protein levels. By contrast, in MDA468 cells, synergy between the two compounds was not observed. Therefore, the pausing epigenetic signature was permissive for synergy between SAHA and PJ34 on TXNIP gene expression. The synergy between SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis. In MDA157 cells, but not in MDA468 cells, combined treatment of SAHA and PJ34 induced a decrease in cell viability and an increase of apoptosis. Thus, our data support the hypothesis that TXNIP is an effective target for the treatment of breast cancer.

show abstract

Section: Discussionmentioning

confidence: 80%

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…VPA initially used for epilepsy treatment was demonstrated to also act as a HDAC inhibitor (Gottlicher et al, 2001;Phiel et al, 2001). Although, the combination of VPA and decitabine reactivates hypermethylated genes as demonstrated by re-expressing fetal haemoglobin, this combination is limited by toxicity, specifically by neurological symptoms in patients with non-small cell lung cancer (Chu et al, 2013). Another HDAC inhibitor, sodium butyrate, when combined with 5-azadC, inhibited mammary tumourigenesis in a murine model (Elangovan et al, 2013).…”

Section: Combination Of 5-azac and 5-azadc And Histone Deacetylase (Hmentioning

confidence: 99%

DNA demethylation and invasive cancer: implications for therapeutics

Cheishvili

Boureau

Szyf

2015

British J Pharmacology

View full text Add to dashboard Cite

One of the hallmarks of cancer is aberrant DNA methylation, which is associated with abnormal gene expression. Both hypermethylation and silencing of tumour suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. As DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumour suppressor genes. Two cytosine analogues, 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine, were approved by the Food and Drug Administration as antitumour agents in 2004 and 2006 respectively. However, these agents might cause activation of a panel of prometastatic genes in addition to activating tumour suppressor genes, which might lead to increased metastasis. This poses the challenge of how to target tumour suppressor genes and block cancer growth with DNA-demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead. LINKED ARTICLESThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-11 Abbreviations 5-azaC, 5-azacytidine; 5-azadC, 5-aza-2′-deoxycytidine; FDA, Food and Drug Administration; HDAC, histone deacetylase; SAH, S-adenosyl-homocysteine; SAHA, suberoylanilide hydroxamic acid; SAM, S-adenosyl-methionine Tables of Links DNA methylation overviewDNA methylation is an enzymatically catalysed covalent modification of DNA, occurring typically in the context of cytosine-phosphate-guanine (CpG) dinucleotides. In general, regions with high CpG content, named CpG islands, are demethylated in normal cells, whereas regions with an intermediate or low density of CpGs are differentially methylated in some tissues, but not in others (Bird et al., 1985). Although rarely observed, non-CpG methylation is mainly found in embryonic stem cells (Lister et al., 2009), but its function needs to be further explored. However, non-CpG methylation is abundant in adult brains, and recent data suggest that it plays a role in silencing promoter activity similar to CpG methylation (Guo et al., 2013;Lister et al., 2013). DNA methyltransferases (DNMTs) catalyse the transfer of a methyl group from its donor S-adenosine-methionine (SAM) to the cytosine nucleotide of DNA. Three distinct phylogenic DNMTs were identified in mammals. DNMT1 is a maintenance DNMT, which shows preference for hemimethylated DNA in vitro and faithfully copies DNA methylation in a cytosine-guanine (CG) palindromic dinucleotide from the parental strand to the daughter strand during cell division (Zucker et al., 1985;Flynn et al., 1996;Pradhan et al., 1999;Fatemi et al., 2001). DNMT3a and DNMT3b methylate unmethylated and hemimethylated DNA at an equal rate, which is consistent with a de novo methylation function (Okano et ...

show abstract

“…Decitabine (5‐aza‐2′‐deoxycytidine) is the only HMA approved by the China Food and Drug Administration. The concentration required to reverse tumor‐specific DNA methylation is much lower than that needed to produce maximal cytotoxicity 18, 19, 20. The apparent reversibility of resistance by epigenetic interference has the potential to turn the arrow of time backwards, replacing progression with regression, and thus provides a good rational for the use of low‐dose decitabine as an antidote to the resistance to current standard chemotherapies and as a blueprint to significantly extend patient survival 11, 16, 17…”

Section: Introductionmentioning

confidence: 99%

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen

Nie

Liu

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty‐five patients received either the 5‐day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine‐primed chemotherapy, D‐C cohort) or the aforementioned regimen followed by cytokine‐induced killer cells therapy (D‐C and cytokine‐induced killer [CIK] cell treatment, D‐C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment‐related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment‐free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D‐C + CIK cohort. Consistently, the progression‐free survival (PFS) of the D‐C + CIK cohort compared favorably to the best PFS of the pre‐resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non‐significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large‐scale evaluation of drug‐resistant R/R AT cancer patients with advanced stage disease.

show abstract

Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer

Cited by 78 publications

References 31 publications

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

DNA demethylation and invasive cancer: implications for therapeutics

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Contact Info

Product

Resources

About