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 4998

Special Issue Editors


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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

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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

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Keywords

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

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Published Papers (4 papers)

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Research

13 pages, 989 KiB  
Article
Molecular Interactions of the Plant Steroid Hormone Epibrassinolide on Human Drug-Sensitive and Drug-Resistant Small-Cell Lung Carcinoma Cells
by David Sadava and Shiuan Chen
Cancers 2024, 16(22), 3812; https://doi.org/10.3390/cancers16223812 - 13 Nov 2024
Viewed by 496
Abstract
Background: Small-cell lung cancer (SCLC) has a poor prognosis because it is often diagnosed after it has spread and develops multi-drug resistance. Epibrassinolide (EB) is a plant steroid hormone with widespread distribution and physiological effects. In plants, EB-activated gene expression occurs via a [...] Read more.
Background: Small-cell lung cancer (SCLC) has a poor prognosis because it is often diagnosed after it has spread and develops multi-drug resistance. Epibrassinolide (EB) is a plant steroid hormone with widespread distribution and physiological effects. In plants, EB-activated gene expression occurs via a GSK-mediated signaling pathway, similar to Wnt-β-catenin signaling in animal cells that is elevated in cancer cells. Methods: This mechanistic parallel prompted investigations of the molecular interactions of EB on drug-sensitive (H69) and multi-drug-resistant (VPA) SCLC cells. Cellular and molecular investigations were performed. Results: Pharmacologic interactions between EB and the Wnt signaling inhibitors IGC-011 and PRI-724 were determined by the combination index method and showed antagonism, indicating that EB acts on the same pathway as these inhibitors. Following incubation of drug-sensitive and drug-resistant SCLC cells with EB, there was a reduction in β-catenin (e.g., 3.8 to 0.7 pg/µg protein), accompanied by a reduction in β-catenin promoter activity, measured by firefly luciferase-coupled promoter element transfection. Cellular β-catenin concentration is regulated by the active form of GSK3β. In Wnt signaling, active GSK3β is converted to inactive pGSK3β, thereby increasing the concentration of β-catenin. After incubation of SCLC cells with EB, there was a reduction in the inactive form (pGSK3β) and a relative increase in the active form (GSK3β). In vitro enzyme assays showed that EB did not inhibit purified GSK3β, but there was non-competitive inhibition when SCLC cell extracts were used as the source of enzyme. This indirect inhibition by EB indicates that it may act on the Wnt pathway by blocking the phosphorylation of GSK3β. The protein levels of three SCLC tumor markers, namely, NSE, CAV1, and MYCL1, were elevated in drug-resistant SCLC cells. EB incubation led to a significant reduction in the levels of the three markers. Two major effects of EB on SCLC cells are the promotion of apoptosis and the reversal of drug resistance. Transcriptional analyses showed that after exposure of SCLC cells to EB, there were increases in the expression of genes encoding apoptotic inducers (e.g., BAX and FAS) and effectors (e.g., CASP3) and reductions in the expression of genes encoding apoptosis inhibitors (e.g., survivin). PGP1 and MRP1, two membrane efflux pumps expressed in SCLC cells, were elevated in drug-resistant cells, but EB incubation did not affect these protein levels. Cellular assays of drug efflux by PGP1 showed an increase in drug-resistant cells, but EB did not alter efflux activity. Following exposure to human liver microsomes, EB was metabolized by NADPH-dependent oxidation and UDPG-dependent glucuronidation, as evidenced by the elimination of EB cytotoxicity against SCLC cells. Conclusions: Taken together, these data indicate that EB, a steroid hormone in plants consumed in the human diet, is pharmacologically active in drug-sensitive and drug-resistant SCLC cells in the Wnt signaling pathway, alters apoptotic gene expression, and is a substrate for microsomal modifications. Full article
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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 1236
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
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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 1380
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
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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 1386
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
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