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Cancers
Special Issues
Cancer Drug Resistance: An Epigenetic Approach
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Cancer Drug Resistance: An Epigenetic Approach

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 9207

Special Issue Editor

Dr. Aamir Ahmad

E-Mail Website
Guest Editor
Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Interests: cancer epigenetics; metastasis; cancer drug resistance; tumor microenvironment; miRNA; non-coding RNAs; cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Resistance to therapies, particularly acquired resistance, remains a major challenge in the clinical management of cancer patients. Most of the research on the subject has been dedicated to the evaluation of changes in gene(s) or the protein(s) expression that accompany acquired drug resistance. However, recent years have witnessed a change in this approach, with many studies evaluating the epigenetic basis of such resistance. Changes in methylation and/or acetylation patterns as well as regulations involving non-coding RNAs such as, miRNAs, lncRNAs, piRNAs etc. induce heritable phenotypic changes without altering the DNA sequence, and thus define the essence of epigenetic regulation. These epigenetic changes profoundly affect the altered expression of tumor suppressors as well as oncogenes, and therefore the interest in drugs that target the epigenome is much higher now than ever before. The proposed Special Issue will focus on all aspects of epigenetics as applicable to the phenomenon of cancer drug resistance, from understanding the origins to exploitation of the gained knowledge for the development of novel targeted therapies.

Dr. Aamir Ahmad
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer drug resistance
  • epigenetics
  • methylation
  • acetylation
  • miRNA
  • long non-coding RNA

Published Papers (3 papers)

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Research

15 pages, 8104 KiB  
Article
Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance
by Maxime Cahuzac, Benjamin Péant, Anne-Marie Mes-Masson and Fred Saad
Cancers 2022, 14(16), 3877; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14163877 - 11 Aug 2022
Cited by 3 | Viewed by 3008
Abstract
Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) were initially deployed to target breast and ovarian tumors with mutations in DNA damage response genes. Recently, PARPi have been shown to be beneficial in the treatment of prostate cancer (PC) patients having exhausted conventional therapeutics. Despite [...] Read more.
Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) were initially deployed to target breast and ovarian tumors with mutations in DNA damage response genes. Recently, PARPi have been shown to be beneficial in the treatment of prostate cancer (PC) patients having exhausted conventional therapeutics. Despite demonstrating promising response rates, all patients treated with PARPi eventually develop resistance. However, PARPi resistance in PC is not well understood, and further studies are required to understand PARPi resistance in PC to propose strategies to circumvent resistance. Methods: Starting from well-established olaparib-sensitive PC cell lines (LNCaP, C4-2B and DU145), we derived olaparib-resistant (OR) PC cell lines and performed a microarray analysis. Results: The olaparib IC50 values of OR cell lines increased significantly as compared to the parental cell lines. Gene expression analyses revealed that different pathways, including DNA repair, cell cycle regulation and autophagy, were affected by acquired resistance. A total of 195 and 87 genes were significantly upregulated and downregulated, respectively, in all three OR cell lines compared to their parental counterparts. Among these genes, we selected BRCC3, ROCK2 and ATG2B for validation. We showed that ROCK2 expression, basal autophagy and homologous recombination (HR) efficiency were increased in all OR cell lines. Conclusions: Our study provides a new in vitro model to study PARPi resistance in PC and suggests new possible targets to reverse resistance and prolong the benefits of PARPi treatment. Full article
(This article belongs to the Special Issue Cancer Drug Resistance: An Epigenetic Approach)
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20 pages, 1652 KiB  
Article
Activation of ABCC Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines
by Maciej Sobczak, Magdalena Strachowska, Karolina Gronkowska and Agnieszka Robaszkiewicz
Cancers 2022, 14(4), 894; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040894 - 11 Feb 2022
Cited by 11 | Viewed by 2723
Abstract
Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from [...] Read more.
Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from intracellular compartments. To test the possible molecular basis of increased expression of ABCC subfamily members in a cisplatin therapy mimicking model, we generated two cisplatin-resistant cell lines derived from non-small cell lung cancer cells (A549) and triple-negative breast cancer cells (MDA-MB-231). Analysis of data for A549 cells deposited in UCSC Genome Browser provided evidence on the negative interdependence between the occurrence of the CoREST complex at the gene promoters and the overexpression of ABCC genes in cisplatin-resistant lung cancer cells. Pharmacological inhibition of CoREST enzymatic subunits—LSD1 and HDACs—restored gene responsiveness to cisplatin. Overexpression of CoREST-free ABCC10 in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the ABCC10 promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of ABCC10 was only possible in the presence of p53. In summary, the CoREST complex prevents the overexpression of some multidrug resistance proteins from the ABCC subfamily in cancer cells exposed to cisplatin. p53-mediated activation of some ABCC genes by EP300 occurs once their promoters are devoid of the CoREST complex. Full article
(This article belongs to the Special Issue Cancer Drug Resistance: An Epigenetic Approach)
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30 pages, 47082 KiB  
Article
Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through ATM Methylation
by Sun Hee Lee, Su Jin Choi, Wonhyeok Choi, Subin Cho, Miyeon Cho, Dong Sun Kim, Byung Woog Kang, Jong Gwang Kim, You Mie Lee, Hyosun Cho and Hyojeung Kang
Cancers 2021, 13(17), 4252; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174252 - 24 Aug 2021
Cited by 1 | Viewed by 2116
Abstract
Epstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region [...] Read more.
Epstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region are one of the major regions in which DNA methylation controls gene transcription. Despite cisplatin-based chemotherapy being one of the standard treatment regimens for advanced gastric cancer, including EBVaGC, cisplatin alone or in combination with 5-fluorouracil has been limited by its less potent anticancer activity and the occurrence of cisplatin resistance. Accordingly, the current study evaluated the anticancer activities of a combination of cisplatin and 5-Azacytidine (5-AZA) against EBVaGC. Our findings showed that cisplatin upregulated the DNMT3A gene, whereas shRNA-targeted removal of DNMT3A mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of DNMT3A mRNA upregulated the ATM gene through DNA demethylation on the ATM promoter. Furthermore, CRISPR/Cas9-targeted removal of the ATM gene resulted in significantly reduced cell susceptibility and EBV lytic reactivation by a combination of cisplatin and DNMT3A inhibitor 5-AZA. Finally, 5-AZA exhibited a synergistic effect with cisplatin in anti-EBV and anti-EBVaGC activities by increasing drug susceptibility and EBV lytic reactivation. The aforementioned results suggest that cisplatin combined with DNA methylation inhibitors could be a novel therapeutic approach for EBVaGC. Full article
(This article belongs to the Special Issue Cancer Drug Resistance: An Epigenetic Approach)
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