Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid

Forthun, Rakel Brendsdal; SenGupta, Tanima; Skjeldam, Hanne K.; Lindvall, Jessica M.; McCormack, Emmet; Gjertsen, Bjørn Tore; Nilsen, Hilde

doi:10.1371/journal.pone.0048992

Cited by 17 publications

(16 citation statements)

References 51 publications

(69 reference statements)

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“…Inhibition of HSPA1A by KNK-437 could resensitize cells to VPAinduced apoptosis [162]. Furthermore, the phosphoproteins MAPKAPK2, ACTB, HSP90AA1 and HSP90AB1 were considered resistance hubs in VPA-resistant AML cell lines [163]. Altered levels of antiapoptotic proteins drive resistance against HDACi-mediated apoptosis.…”

Section: Drug Resistance Mechanismsmentioning

confidence: 99%

Role of HDACs in normal and malignant hematopoiesis

2020

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Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

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Section: Drug Resistance Mechanismsmentioning

confidence: 99%

Role of HDACs in normal and malignant hematopoiesis

2020

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“…The concept of dual Plk1 and BRD4 inhibition may be interesting in light of ongoing trials with epigenetic modulators. 73 The histone deacteylase inhibitor valproic acid has been shown to upregulate trimethylation of histone H3 lysine 27 in AML cells, 74 and may be an interesting drug for volasertib combination therapy.…”

Section: Potential Biomarkers Of Volasertib Sensitivitymentioning

confidence: 99%

Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy

2014

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Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in oncology. In recent years, several Plk1 inhibitors have been developed, with some agents showing encouraging results in early-phase clinical trials. This review focuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor. Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer. Trials performed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the most promising results seen in patients with acute myeloid leukemia (AML). Encouragingly, recent phase II data have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone in patients with previously untreated AML. Based on these observations, and its presumably manageable safety profile, volasertib is currently in phase III development as a potential treatment for patients with AML who are ineligible for intensive remission induction therapy. Given that many patients with AML are of an older age and frail, this constitutes an area of major unmet need. In this review, we discuss the biologic rationale for Plk1 inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the future identification of biomarkers that might predict response to volasertib and help determine the role of this agent in the clinic.

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“…For example, C. elegans DNA repair proteins respond to DNA damage by instigating a survival program closely resembling that in human tissues [ 49 , 50 , 51 ]. Moreover, recent investigations have identified novel C. elegans proteins counteracting cytotoxic effects both of fluoropyrimidine and HDAC inhibitor agents [ 52 , 53 , 54 ]. In the planned validation experiments, we intend to use molecular imaging, reverse and forward genetics, and chemical genetics in functional assays for relevant endpoints (apoptosis, necrosis, heat-shock sensitivity, and others that apply).…”

Section: Prediction Of Toxicity In Cancer Therapy—integration Of Mmentioning

confidence: 99%

Biomarkers of Treatment Toxicity in Combined-Modality Cancer Therapies with Radiation and Systemic Drugs: Study Design, Multiplex Methods, Molecular Networks

Ree

Meltzer

Flatmark

et al. 2014

IJMS

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Organ toxicity in cancer therapy is likely caused by an underlying disposition for given pathophysiological mechanisms in the individual patient. Mechanistic data on treatment toxicity at the patient level are scarce; hence, probabilistic and translational linkages among different layers of data information, all the way from cellular targets of the therapeutic exposure to tissues and ultimately the patient’s organ systems, are required. Throughout all of these layers, untoward treatment effects may be viewed as perturbations that propagate within a hierarchically structured network from one functional level to the next, at each level causing disturbances that reach a critical threshold, which ultimately are manifested as clinical adverse reactions. Advances in bioinformatics permit compilation of information across the various levels of data organization, presumably enabling integrated systems biology-based prediction of treatment safety. In view of the complexity of biological responses to cancer therapy, this communication reports on a “top-down” strategy, starting with the systematic assessment of adverse effects within a defined therapeutic context and proceeding to transcriptomic and proteomic analysis of relevant patient tissue samples and computational exploration of the resulting data, with the ultimate aim of utilizing information from functional connectivity networks in evaluation of patient safety in multimodal cancer therapy.

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Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid

Cited by 17 publications

References 51 publications

Role of HDACs in normal and malignant hematopoiesis

Role of HDACs in normal and malignant hematopoiesis

Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy

Biomarkers of Treatment Toxicity in Combined-Modality Cancer Therapies with Radiation and Systemic Drugs: Study Design, Multiplex Methods, Molecular Networks

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