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What are the main claims of the paper and how important are they?
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Are these claims novel? If not, please specify papers that weaken the claims to the originality of this one.
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Are the claims properly placed in the context of the previous literature?
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Do the results support the claims? If not, what other evidence is required?
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If a protocol is provided, for example for a randomized controlled trial, are there any important deviations from it? If so, have the authors explained adequately why the deviations occurred?
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Is the methodology valid? Does the paper offer enough details of its methodology that its experiments or its analyses could be reproduced?
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Would any other experiments or additional information improve the paper? How much better would the paper be if this extra work was done, and how difficult would such work be to do, or to provide?
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Is this paper outstanding in its discipline? (For example, would you like to see this work presented in a seminar at your hospital or university? Do you feel these results need to be incorporated in your next general lecture on the subject?) If yes, what makes it outstanding? If not, why not?
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Other Comments:
This is an excellent publication, because it emphasizes that
up-regulation of energy metabolism is a key feature of proliferating cells from cancers and leukemias. Thus, targeting of metabolic pathways represents a therapeutic challenge involving both dietary and drug-mediated strategies. Considering the increasing importance of epigenetically active drugs, this study has evaluate the impact of the DNA-methyltransferase-inhibitor 5-desoxy-2-azacytidine (Decitabine, DAC) and the histone-deacetylase-inhibitor suberoyl anilide hydroxamic acid (SAHA, Vorinostat) on malignancy-associated pathways such as carbohydrate- and fat- metabolism.
A comparison of both leukemia cell lines to normal CD34+ cells confirmed a malignancy-associated stimulation of energy metabolism. Although epigenetic drugs could downregulate just a few singular metabolism- associated genes such as CS (citrate synthase), a global evaluation on pathways demonstrated a significant drug-mediated downregulation of the intra-mitochondrial pathways, namely the tri-carbonic acid cycle and beta oxidation and to a lesser extent also cytoplasmic glycolysis. No significant impact on aerobic glycolysis (Warburg effect) could be detected in this study.
The observation that the KG1 cell line reacted more sensitive to demethylating drugs than the HL60 cell line, where drug treatment selected for survival of differentiated cells, may support application of DAC and SAHA to leukemias with an undifferentiated phenotype but also with the potential to induce differentiation. Efficient targeting of intra-mitochondrial pathways appears to be associated with multiple pro-apoptotic activities of these drugs which may also have far-reaching clinical consequences -
Competing interests:
None
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Invited by the author to review this article? :
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Have you previously published on this or a similar topic?:
Yes
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References:
Ghanim V, Herrmann H, Heller G, Peter B, Hadzijusufovic E, Blatt K, Schuch K, Cerny-Reiterer S, Mirkina I, Karlic H, Pickl WF, Zöchbauer-Müller S, Valent P. 5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand Blood. 2012;119(18):4242-5 Stefanska B, Karlic H, Varga F, Fabianowska-Majewska K, Haslberger A. G. Epigenetic mechanisms in anticancer actions of bioactive food components – the implications in cancer prevention and therapy. Br J Pharmacol. 2012 167:279-97
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Experience and credentials in the specific area of science:
I am a Professor fro Experimental Hematology with 30 years experience in this subject
- How to cite: Karlic H .Epigenetically active drugs target metabolic gene-regulation in leukemic cells[Review of the article 'Epigenetically active drugs target metabolic gene-regulation in leukemic cells ' by Karlic H].WebmedCentral 2013;4(9):WMCRW002858
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The major claim is the insight on the activity of the Epigenetics drugs in the energy pathways in leukemic cells
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Yes they are.
Yes
There is not a protocol provided because this is only a laboratory study
Yes
No
Yes
This is an excellent publication, because it emphasizes that:
1. up-regulation of energy metabolism is a key feature of proliferating cells from cancers and leukemias. Thus, targeting of metabolic pathways represents a therapeutic challenge involving drug-mediated strategies. This is very important in the epigenetic therapy setting. Moreover we have not a full undestending of epigenetic therapy action and I think that this study has the claim to underline the impact of the DNA-methyltransferase-inhibitor 5-desoxy-2-azacytidine (Decitabine, DAC) and the histone-deacetylase-inhibitor suberoyl anilide hydroxamic acid (SAHA, Vorinostat) on malignancy-associated pathways such as carbohydrate- and fat- metabolism.
2. Finally, the Authors used to different cell-lines and observed a different activity of the drugs. In particular they observed that the KG1 cell line reacted more to demethylating drugs than the HL60 cell line, where drug treatment selected for survival of differentiated cells. This observation can support the application of DAC and SAHA to undifferentiated leukemik phenotype in the context of a full dose chemotherapy.
No
Yes
Patriarca et al. TET2 mutations in Ph-negative myeloproliferative neoplasms: identification of three novel mutations and relationship with clinical and laboratory findings. Biomed Res Int. 2013;2013:929840. doi: 10.1155/2013/929840. Epub 2013 May 25.
I have been clinical researched in the Myeloid disease molecular biology in the last 6 years.