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A novel study of polyamides’ therapeutic potential as transcription factor inhibitors in CML

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Year: 2018
COI code: CIGS15_668
Paper Language: English

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Authors A novel study of polyamides’ therapeutic potential as transcription factor inhibitors in CML

Kourosh Hayatigolkhatmi - Paul O Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
Giacomo Padroni - Department of Pure and Applied Chemistry University of Strathclyde, Thomas Graham Building, Glasgow, UK.
wu su - Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, P. R. China.
Lijing Fang - Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, P. R. China.
Eduardo Gómez-Castañeda - Paul O Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
Ya-Ching Hsieh - Paul O Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.

Abstract:

Introduction: Despite clinical success of tyrosine kinase inhibitors (TKI) in chronic phase (CP) CML patients, nearly all have minimal residual disease owing to persistent, primitive, leukaemia stem cells (LSC). E2F transcription factor 1 (E2F1) is a critical survival factor for TKI resistant LSC. Polyamides (PA) that target specific DNA sequences have a successful history of inhibiting transcription factors (TFs).Purpose: To investigate synthetic programmed PA’s ability to inhibit E2F1 transcriptional activity so causing CML cell death.Methods: Blast crisis (BC) KCL22 cells and CP CML CD34+ cells were assessed after treatment with PA, TKI or their combination. Assessment methods included: cell density by dye exclusion; flow cytometry for apoptosis, proliferation and cell cycle status; gene expression by RT-qPCR; and colony forming cell (CFC) assay with clonogenic primary CP CML CD34+cells.Results: Our global gene expression analysis revealed significant down-regulation of TRIM45 and RARS2 with PA treatment. TRIM45 has an established role in proliferation, development, oncogenesis, and apoptosis. In addition, our PA successfully inhibited CP/BC CML cell growth based on cell density and flow cytometry analysis compared to untreated control. Indeed the combination of PA with nilotinib had the potential of increasing nilotinib efficacy in killing CP CML cells. CFC assay showed reduction in colony formation of CP CML cells.Conclusion: Going forward, this technology could enable a systematic ‘DNA-binding scan’ providing a detailed map of genes under E2F1 control in CML LSCs that could assist in the development of TF inhibitors as novel therapeutic alternatives in the disease.

Keywords:

Polyamide, Chronic Myeloid Leukaemia, CML, E2F1, TKI.

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COI code: CIGS15_668

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Hayatigolkhatmi, Kourosh; Giacomo Padroni; wu su; Lijing Fang; Eduardo Gómez-Castañeda & Ya-Ching Hsieh, 2018, A novel study of polyamides’ therapeutic potential as transcription factor inhibitors in CML, The Third International and 15th National Genetics Congress, تهران, انجمن علمي ژنتيك ايران, https://www.civilica.com/Paper-CIGS15-CIGS15_668.htmlInside the text, wherever referred to or an achievement of this article is mentioned, after mentioning the article, inside the parental, the following specifications are written.
First Time: (Hayatigolkhatmi, Kourosh; Giacomo Padroni; wu su; Lijing Fang; Eduardo Gómez-Castañeda & Ya-Ching Hsieh, 2018)
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