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Cancers
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Cancer Drug Discovery and Development Targeting Epigenetics, Metabolism, and DNA...
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Cancer Drug Discovery and Development Targeting Epigenetics, Metabolism, and DNA Repair

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

Deadline for manuscript submissions: 31 January 2025 | Viewed by 2483

Special Issue Editors

Dr. Vikas V. Dukhande

E-Mail Website
Guest Editor
Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA
Interests: cancer metabolism; cell death; cancer epigenetics; ubiquitination; insulin signaling
Dr. Aditi Jain

E-Mail Website
Guest Editor
Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA
Interests: DNA damage and repair; pancreatic and GI cancers; synthetic lethality; precision medicine; novel therapeutics and drug resistance

Special Issue Information

Dear Colleagues,

Cancer is a leading cause of mortality worldwide. Over the last 25 years, we have ushered in the era of precision oncology with targeted therapeutics, immunotherapy, and gene therapy. However, the need for prevention, early detection, biomarkers, therapeutics, and medical interventions is still immense and is highlighted by programs like the Cancer Moonshot project. Research on established and emerging cancer hallmarks can provide breakthroughs that will benefit cancer patients.

We are pleased to invite you to submit original research and review articles on drug research and development tackling cancer hallmarks such as epigenetics, deregulated metabolism, genome instability, and the crosstalk between them. There are several FDA-approved drugs on the market that target these hallmarks; however, the field is still in its infancy when it comes to discovering novel targets and developing drugs directed at them.

In this Special Issue, original research articles and reviews are welcome. We are seeking research topics in cancer biology/cancer pharmacology that may include, but are not limited to, the following:

  • Discovery and development of novel molecules targeting epigenetics and metabolism in cancer;
  • Drug development and synthetic lethal strategies involving epigenetics and DNA damage responses;
  • Combination approaches, drug repurposing, and strategies to overcome drug resistance, focusing on cancer epigenetics, metabolism, and DNA repair;
  • Mechanistic approaches to targets and drugs acting on cancer epigenetics, metabolism, and DNA repair;
  • Target discovery in the field of cancer epigenetics, metabolism, and DNA repair;
  • Crosstalk between cancer epigenetics and metabolism and/or epigenetics and DNA repair.

We hope that this Special Issue will highlight and amalgamate novel targets, drug discovery, and development efforts in epigenetics, deregulated metabolism, and DNA repair in cancer. We look forward to receiving your contributions.

Dr. Vikas V. Dukhande
Dr. Aditi Jain
Guest Editors

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 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

  • apoptosis
  • bromodomain proteins
  • cancer epigenetics
  • cancer metabolism
  • DNA methylation
  • DNA repair
  • epigenetic therapeutics
  • histone modifications
  • metabolic inhibitors
  • Warburg effect

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (3 papers)

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Research

24 pages, 11916 KiB  
Article
Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells
by Shraddha Bhutkar, Anjali Yadav, Himaxi Patel, Shrikant Barot, Ketan Patel and Vikas V. Dukhande
Cancers 2024, 16(15), 2713; https://doi.org/10.3390/cancers16152713 - 30 Jul 2024
Viewed by 461
Abstract
The current 5-year survival rate of pancreatic cancer is about 12%, making it one of the deadliest malignancies. The rapid metastasis, acquired drug resistance, and poor patient prognosis necessitate better therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC). Multiple studies show that combining chemotherapeutics [...] Read more.
The current 5-year survival rate of pancreatic cancer is about 12%, making it one of the deadliest malignancies. The rapid metastasis, acquired drug resistance, and poor patient prognosis necessitate better therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC). Multiple studies show that combining chemotherapeutics for solid tumors has been successful. Targeting two distinct emerging hallmarks, such as non-mutational epigenetic changes by panobinostat (Pan) and delayed cell cycle progression by abemaciclib (Abe), inhibits pancreatic cancer growth. HDAC and CDK4/6 inhibitors are effective but are prone to drug resistance and failure as single agents. Therefore, we hypothesized that combining Abe and Pan could synergistically and lethally affect PDAC survival and proliferation. Multiple cell-based assays, enzymatic activity experiments, and flow cytometry experiments were performed to determine the effects of Abe, Pan, and their combination on PDAC cells and human dermal fibroblasts. Western blotting was used to determine the expression of cell cycle, epigenetic, and apoptosis markers. The Abe-Pan combination exhibited excellent efficacy and produced synergistic effects, altering the expression of cell cycle proteins and epigenetic markers. Pan, alone and in combination with Abe, caused apoptosis in pancreatic cancer cells. Abe-Pan co-treatment showed relative safety in normal human dermal fibroblasts. Our novel combination treatment of Abe and Pan shows synergistic effects on PDAC cells. The combination induces apoptosis, shows relative safety, and merits further investigation due to its therapeutic potential in the treatment of PDAC. Full article
(This article belongs to the Special Issue Cancer Drug Discovery and Development Targeting Epigenetics, Metabolism, and DNA Repair)
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20 pages, 8986 KiB  
Article
Sanguinarine Induces Necroptosis of HCC by Targeting PKM2 Mediated Energy Metabolism
by Rui Kong, Nan Wang, Chunli Zhou, Yuqing Zhou, Xiaoyan Guo, Dongyan Wang, Yihai Shi, Rong Wan, Yuejuan Zheng and Jie Lu
Cancers 2024, 16(14), 2533; https://doi.org/10.3390/cancers16142533 - 13 Jul 2024
Viewed by 805
Abstract
Backgrounds: Abnormal metabolism is the hallmark of hepatocellular carcinoma. Targeting energy metabolism has become the major focus of cancer therapy. The natural product, sanguinarine, displays remarkable anti-tumor properties by disturbing energy homeostasis; however, the underlying mechanism has not yet been elucidated. Methods: The [...] Read more.
Backgrounds: Abnormal metabolism is the hallmark of hepatocellular carcinoma. Targeting energy metabolism has become the major focus of cancer therapy. The natural product, sanguinarine, displays remarkable anti-tumor properties by disturbing energy homeostasis; however, the underlying mechanism has not yet been elucidated. Methods: The anticancer activity of sanguinarine was determined using CCK-8 and colony formation assay. Morphological changes of induced cell death were observed under electron microscopy. Necroptosis and apoptosis related markers were detected using western blotting. PKM2 was identified as the target by transcriptome sequencing. Molecular docking assay was used to evaluate the binding affinity of sanguinarine to the PKM2 molecule. Furthermore, Alb-CreERT2; PKM2loxp/loxp; Rosa26RFP mice was used to construct the model of HCC—through the intervention of sanguinarine in vitro and in vivo—to accurately explore the regulation effect of sanguinarine on cancer energy metabolism. Results: Sanguinarine inhibited tumor proliferation, metastasis and induced two modes of cell death. Molecular docking of sanguinarine with PKM2 showed appreciable binding affinity. PKM2 kinase activity and aerobic glycolysis rate declined, and mitochondrial oxidative phosphorylation was inhibited by sanguinarine application; these changes result in energy deficits and lead to necroptosis. Additionally, sanguinarine treatment prevents the translocation of PKM2 into the nucleus and suppresses the interaction of PKM2 with β-catenin; the transcriptional activity of PKM2/β-catenin signaling and its downstream genes were decreased. Conclusions: Sanguinarine showed remarkable anti-HCC activity via regulating energy metabolism by PKM2/β-catenin signaling. On the basis of these investigations, we propose that sanguinarine might be considered as a promising compound for discovery of anti-HCC drugs. Full article
(This article belongs to the Special Issue Cancer Drug Discovery and Development Targeting Epigenetics, Metabolism, and DNA Repair)
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16 pages, 3314 KiB  
Article
Small-Molecule Inhibition of CBX4/7 Hypersensitises Homologous Recombination-Impaired Cancer to Radiation by Compromising CtIP-Mediated DNA End Resection
by Hugh C. Osborne, Benjamin M. Foster, Hazim Al-Hazmi, Stefan Meyer, Igor Larrosa and Christine K. Schmidt
Cancers 2024, 16(11), 2155; https://doi.org/10.3390/cancers16112155 - 6 Jun 2024
Viewed by 886
Abstract
The therapeutic targeting of DNA repair pathways is an emerging concept in cancer treatment. Compounds that target specific DNA repair processes, such as those mending DNA double-strand breaks (DSBs), are therefore of therapeutic interest. UNC3866 is a small molecule that targets CBX4, a [...] Read more.
The therapeutic targeting of DNA repair pathways is an emerging concept in cancer treatment. Compounds that target specific DNA repair processes, such as those mending DNA double-strand breaks (DSBs), are therefore of therapeutic interest. UNC3866 is a small molecule that targets CBX4, a chromobox protein, and a SUMO E3 ligase. As a key modulator of DNA end resection—a prerequisite for DSB repair by homologous recombination (HR)—CBX4 promotes the functions of the DNA resection factor CtIP. Here, we show that treatment with UNC3866 markedly sensitises HR-deficient, NHEJ-hyperactive cancer cells to ionising radiation (IR), while it is non-toxic in selected HR-proficient cells. Consistent with UNC3866 targeting CtIP functions, it inhibits end-resection-dependent DNA repair including HR, alternative end joining (alt-EJ), and single-strand annealing (SSA). These findings raise the possibility that the UNC3866-mediated inhibition of end resection processes we define highlights a distinct vulnerability for the selective killing of HR-ineffective cancers. Full article
(This article belongs to the Special Issue Cancer Drug Discovery and Development Targeting Epigenetics, Metabolism, and DNA Repair)
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