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Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy
College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates; Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates; Pharmacology, Clinical Biochemistry and Molecular Biology Units, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt; College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
Pharmacology, Clinical Biochemistry and Molecular Biology Units, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
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2015 (English)In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 16, no 7, p. 1056-1070Article in journal (Refereed) Published
Abstract [en]

Lung cancer cells show inherent and acquired resistance to chemotherapy. The lack of good predictive markers/novel targets and the incomplete understanding of the mechanisms of resistance limit the success of lung cancer response to chemotherapy. In the present study, we used an isogenic pair of lung adenocarcinoma cell lines; A549 (wild-type) and A549DOX11 (doxorubicin resistant) to study the role of epigenetics and miRNA in resistance/response of non-small cell lung cancer (NSCLC) cells to doxorubicin. Our results demonstrate differential expression of epigenetic markers whereby the level of HDACs 1, 2, 3 and4, DNA methyltransferase, acetylated H2B and acetylated H3 were lower in A549DOX11 compared to A549 cells. Fourteen miRNAs were dys-regulated in A549DOX11 cells compared to A549 cells, of these 14 miRNAs, 4 (has-mir-1973, 494, 4286 and 29b-3p) have shown 2.99 – 4.44 fold increase in their expression. This was associated with reduced apoptosis and higher resistance of A549DOX11cells to doxorubicin and etoposide. Sequential treatment with the epigenetic modifiers trichostatin A or 5-aza-2'-deoxycytidine followed by doxorubicin resulted in: (i) enhanced sensitivity of both cell lines to doxorubicin especially at low concentrations, (ii) enhanced doxorubicin-induced DNA damage in both cell lines, (iii) dysregulation of some miRNAs in A549 cells. In conclusion, A549DOX11 cells resistant to DNA damaging drugs have epigenetic profile and miRNA expression different from the sensitive cells. Moreover, epigenetic modifiers may reverse the resistance of certain NSCLC cells to DNA damaging agents by enhancing induction of DNA damage. This may open the door for using epigenetic profile/miRNA expression of some cancer cells as resistance markers/targets to improve response of resistant cells to doxorubicin and for the use of combination doxorubicin/epigenetic modifiers to reduce doxorubicin toxicity.

Place, publisher, year, edition, pages
Philadelphia, PA, United States: Taylor & Francis, 2015. Vol. 16, no 7, p. 1056-1070
Keywords [en]
doxorubicin; epigenetics; HDAC; miRNA; trichostatin A; 5-aza-20 -deoxycytidine
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-184474DOI: 10.1080/15384047.2015.1046023ISI: 000357699300008PubMedID: 25962089Scopus ID: 2-s2.0-84943743134OAI: oai:DiVA.org:liu-184474DiVA, id: diva2:1653576
Note

Funding: This work was supported by the KEF-HOLDING-FAIZAL and Shabana Foundation and the Boehringer Ingelheim Pharmaceutical company.

Available from: 2022-04-22 Created: 2022-04-22 Last updated: 2022-04-28Bibliographically approved

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El-Serafi, Ahmed Taher

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