A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells

Balch, Curt; Naegeli, Kaleb; Nam, Seungyoon; Ballard, Brett; Hyslop, Alan; Melki, Christina S.; Reilly, Elizabeth; Hur, Man Wook; Nephew, Kenneth P.

doi:10.4161/cbt.20086

Cited by 17 publications

(20 citation statements)

References 69 publications

(166 reference statements)

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“…Similar microRNAs were found altered with the treatment of vorinostat in our ccRCC patients (Figure 4B). Furthermore, vorinostat has been reported to specifically alter miRNA 20a , 142-3p , 199a , let7b , and 365 in ovarian cancer cells (Balch et al , 2012), miRNA 142-3p and 99a in renal cancer cells (Schiffgen et al , 2013), miR-let7b in ras-transformed thyroid cells (Borbone et al , 2013) and lung cancer cells (Lee et al , 2009), and miR-20a in acute myeloid leukaemia cells (Lepore et al , 2013) and liver cancer cells (Yang et al , 2015). Our findings on circulating microRNA and their modulation by vorinostat in ccRCC patients serum is quite interesting.…”

Section: Discussionmentioning

confidence: 99%

Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial

et al. 2017

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Background:Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus.Methods:Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg−1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs.Results:Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1–11.0) and 13.9 months (CI: 9.8–20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit.Conclusions:The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.

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Section: Discussionmentioning

confidence: 99%

Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial

et al. 2017

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“…In addition, PDCD4 enhances chemosensitivity of ovarian cancer cells by activating death receptor pathway in vitro and in vivo (47), and the loss of MLH1 mediated by methylation can lead to the cisplatin-resistance in ovarian cancer (48,49). In addition, EGFR (50,51), ATF1 (52,53) and HNF1A (55) are all associated with drug resistance in ovarian and other types of cancer.…”

Section: Resultsmentioning

confidence: 99%

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Zhang²,

Gao

et al. 2014

Oncology Reports

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Abstract. The expression of HNF1 homeobox B (HNF1B) is associated with cancer risk in several tumors, including ovarian cancer, and its decreased expression play roles in cancer development. However, the study of HNF1B and cancer is limited, and its association with drug resistance in cancer has never been reported. On the basis of array data retrieved from Oncomine and Gene Expression Omnibus (GEO) online database, we found that the mRNA expression of HNF1B in 586 ovarian serous cystadenocarcinomas and in platinum-resistant A2780 epithelial ovarian cancer cells was significantly decreased, indicating a potential role of HNF1B in drug resistance in ovarian cancer. Based on this finding, comprehensive bioinformatics analyses, including protein/ gene interaction, protein-small molecule/chemical interaction, biological process annotation, gene co-occurrence and pathway enrichment analysis and microRNA-mRNA interaction, were performed to illustrate the association of HNF1B with drug resistance in ovarian cancer. We found that among the proteins/ genes, small molecules/chemicals and microRNAs which directly interacted with HNF1B, the majority was associated with drug resistance in cancer, particularly in ovarian cancer. Biological process annotation revealed that HNF1B closely related to 24 biological processes which were all notably associated with ovarian cancer and drug resistance. These results indicated that the downregulation of HNF1B may contribute to drug resistance in ovarian cancer, via its direct interactions with these drug resistance-related proteins/genes, small molecules/chemicals and microRNAs, and via its regulations on the drug resistance-related biological processes. Pathway enrichment analysis of 36 genes which co-occurred with HNF1B, ovarian cancer and drug resistance indicated that the HNF1B may perform its drug resistance-related functions through 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling. Collectively, in this study, we illustrated for the first time that HNF1B may contribute to drug resistance in ovarian cancer, potentially through the 4 pathways. The present study may pave the way for further investigation of the drug resistance-related functions of HNF1B in ovarian cancer.

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“…These regulatory networks introduce potent biomarkers useful for generating testable hypotheses on EMT origin in ILDs or metastatic tumours. On the other hand, WNT signalling and EMT are direct targets of AR42 histone deacetylase inhibitor in ovarian cancer cells where it could downregulate oncogenic miR-30, suggesting that AR42 treatment may reverse EMT-metastasis [88].…”

Section: Mirna-mediated Post-transcriptional Regulation Of the Wnt/b-mentioning

confidence: 99%

Interplay between microRNAs and WNT/β-catenin signalling pathway regulates epithelial–mesenchymal transition in cancer

Ghahhari

Babashah

2015

European Journal of Cancer

214

179

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A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells

Cited by 17 publications

References 69 publications

Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial

Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Interplay between microRNAs and WNT/β-catenin signalling pathway regulates epithelial–mesenchymal transition in cancer

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