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Epigenomes Mar 2021Epigenetic gene silencing by DNA methylation and histone methylation by EZH2 play an important role in the development of acute myeloid leukemia (AML). EZH2 catalyzes...
Epigenetic gene silencing by DNA methylation and histone methylation by EZH2 play an important role in the development of acute myeloid leukemia (AML). EZH2 catalyzes the trimethylation of histone H3-lysine 27-trimethylated (H3K27me3). These epigenetic alterations silence the expression of the genes that suppress leukemogenesis. Reversal of this gene silencing by 5-aza-2'-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methylation, and by 3-deazaneplanocin-A (DZNep), an inhibitor of EZH2, results in synergistic gene reactivation and antileukemic interaction. The objective of this study is to determine if the addition of another epigenetic agent could further enhance the antileukemic action of these inhibitors of DNA and histone methylation. Vitamin C (Vit C) is reported to enhance the antineoplastic action of 5-Aza-CdR on AML cells. The mechanism responsible for this action of Vit C is due to its function as a cofactor of alpha-ketoglutarate-dependent dioxygenases (α-KGDD). The enhancement by Vit C of the catalytic activity of α-KGDD of the ten eleven translocation (TET) pathway, as well as of the Jumonji C histone demethylases (JHDMs), is shown to result in demethylation of DNA and histones, leading to reactivation of tumor suppressor genes and an antineoplastic effect. This action of Vit C has the potential to complement the antileukemic action of 5-Aza-CdR and DZNep. We observe that Vit C remarkably increases the antineoplastic activity of 5-Aza-CdR and DZNep against myeloid leukemic cells. An important step to bring this novel epigenetic therapy to clinical trial in patients with AML is the determination of its optimal dose schedule.
PubMed: 34968294
DOI: 10.3390/epigenomes5020007 -
Expert Review of Anticancer Therapy 2016Gemtuzumab ozogamicin, an anti-tumour antibiotic linked to an anti-CD33 antibody (Mylotarg®), has been well studied in AML in adults but to a lesser extent in children.... (Review)
Review
Gemtuzumab ozogamicin, an anti-tumour antibiotic linked to an anti-CD33 antibody (Mylotarg®), has been well studied in AML in adults but to a lesser extent in children. No review has yet been published on the dose-related toxicity and efficacy of gemtuzumab ozogamicin in pediatric AML patients. Here we looked at 14 studies then scatterplots and linear regressions were used to estimate the relationship between the dose of gemtuzumab and its toxicity and efficacy. A non-significant increase in bilirubin level and in incidence of veno-occlusive disease was seen with higher doses of gemtuzumab ozogamicin when used as single-agent. In terms of efficacy, even a low dose of 3 mg/m(2) of gemtuzumab ozogamicin can have antileukemic effect, but available data do not allow conclusions on its dose-dependency. Data indicate that higher doses of gemtuzumab ozogamicin account for more adverse events. The data do not show that a high dose is required for anti-leukemic efficacy of gemtuzumab ozogamicin. This study also indicates that there seems to be a role for gemtuzumab ozogamicin in the treatment of pediatric AML and further studies are required to assess its optimal dose, schedule and balance between efficacy and side-effects.
Topics: Age Factors; Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Linear Models
PubMed: 26646091
DOI: 10.1586/14737140.2016.1129903 -
International Journal of Environmental... Sep 2014Several obstacles are encountered in conventional chemotherapy, such as drug toxicity and poor stability. Nanotechnology is envisioned as a strategy to overcome these...
Several obstacles are encountered in conventional chemotherapy, such as drug toxicity and poor stability. Nanotechnology is envisioned as a strategy to overcome these effects and to improve anticancer therapy. Nanoemulsions comprise submicron emulsions composed of biocompatible lipids, and present a large surface area revealing interesting physical properties. Chalcones are flavonoid precursors, and have been studied as cytotoxic drugs for leukemia cells that induce cell death by different apoptosis pathways. In this study, we encapsulated chalcones in a nanoemulsion and compared their effect with the respective free compounds in leukemia and in non-tumoral cell lines, as well as in an in vivo model. Free and loaded-nanoemulsion chalcones induced a similar anti-leukemic effect. Free chalcones induced higher toxicity in VERO cells than chalcones-loaded nanoemulsions. Similar results were observed in vivo. Free chalcones induced a reduction in weight gain and liver injuries, evidenced by oxidative stress, as well as an inflammatory response. Considering the high toxicity and the side effects induced generally by all cancer chemotherapies, nanotechnology provides some options for improving patients' life quality and/or increasing survival rates.
Topics: Animals; Antineoplastic Agents; Chalcones; Chlorocebus aethiops; Drug Delivery Systems; Emulsions; In Vitro Techniques; Leukemia; Leukemia L1210; Liver; Male; Mice; Molecular Targeted Therapy; Nanoparticles; Oxidative Stress; Vero Cells
PubMed: 25264679
DOI: 10.3390/ijerph111010016 -
Frontiers in Oncology 2021Acute myeloid leukemia (AML) remains a devastating disease, with low cure rates despite intensive standard chemotherapy regimens. In the past decade, targeted...
Acute myeloid leukemia (AML) remains a devastating disease, with low cure rates despite intensive standard chemotherapy regimens. In the past decade, targeted antileukemic drugs have emerged from research efforts. Nevertheless, targeted therapies are often effective for only a subset of patients whose leukemias harbor a distinct mutational or gene expression profile and provide only transient antileukemic responses as monotherapies. We previously presented single agent and combination preclinical data for a novel 3-carbon-linked artemisinin-derived dimer (3C-ART), diphenylphosphate analog 838 (ART838), that indicates a promising approach to treat AML, given its demonstrated synergy with targeted antileukemic drugs and large therapeutic window. We now report new data from our initial evaluation of a structurally distinct class of 2-carbon-linked dimeric artemisinin-derived analogs (2C-ARTs) with prior documented antimalarial activity. These 2C-ARTs have antileukemic activity at low (nM) concentrations, have similar cooperativity with other antineoplastic drugs and comparable physicochemical properties to ART838, and provide a viable path to clinical development.
PubMed: 35127495
DOI: 10.3389/fonc.2021.790037 -
Molecular Pharmacology Sep 20082-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show...
Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol.
2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-kappaB (NF-kappaB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.
Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Cell Death; Cell Line, Tumor; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Flavonoids; Free Radical Scavengers; Glutathione; Homeostasis; Humans; Intracellular Space; Leukemia; Membrane Potential, Mitochondrial; Mitochondria; NF-kappa B; Nuclear Proteins; Organ Specificity; Oxidation-Reduction; Piperidines; Proto-Oncogene Proteins; Reactive Oxygen Species; Thalidomide; Transcription, Genetic; Tumor Suppressor Proteins
PubMed: 18556456
DOI: 10.1124/mol.107.040808 -
Frontiers in Oncology 2021Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in... (Review)
Review
Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4 and CD8 T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.
PubMed: 33718188
DOI: 10.3389/fonc.2021.624742 -
Haematologica Jun 2018Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to...
Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×10 white blood cells. studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; =0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; =0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; <0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; =0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in -mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with mutation.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Hormonal; Dexamethasone; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Leukocytosis; Male; Middle Aged; Mutation; Nuclear Proteins; Nucleophosmin; Prognosis; Recurrence; Remission Induction; Treatment Outcome; Young Adult
PubMed: 29519869
DOI: 10.3324/haematol.2017.184267 -
Annals of the New York Academy of... Nov 2014Since it was identified in 1963 as the antileukemic agent in guinea pig serum, L-asparaginase (ASNase) has become an integral component of chemotherapy protocols to... (Review)
Review
Since it was identified in 1963 as the antileukemic agent in guinea pig serum, L-asparaginase (ASNase) has become an integral component of chemotherapy protocols to treat patients with acute lymphoblastic leukemia (ALL). Escherichia coli and Erwinia chrysanthemi provide the sources of ASNase used clinically today. From the time ASNase was first introduced into treatment protocols, the 5-year survival rate has increased significantly, particularly in children and adolescents. E. coli-derived ASNase was approved in 1978 to be used as part of a multiagent chemotherapy to treat ALL. However, the development of hypersensitivity in 10-30% of patients often leads to treatment discontinuation. E. chrysanthemi-derived ASNase (referred to herein as ASNase Erwinia chrysanthemi) is immunologically distinct from E. coli ASNase and therefore does not cross-react with the E. coli enzyme. In 2011, ASNase Erwinia chrysanthemi was approved in the United States for patients who develop hypersensitivity to E. coli-derived ASNase. When indicated, a switch from ASNase E. coli to ASNase E. chrysanthemi allows patients to continue to receive treatment and maintain therapeutic levels of ASNase activity. Therapeutic drug monitoring may help ensure that therapeutic enzyme levels are maintained. Pegylated recombinant ASNase Erwinia chrysanthemi is currently being developed to improve pharmacokinetic properties and reduce immunogenicity.
Topics: Animals; Antineoplastic Agents; Asparaginase; Clinical Trials as Topic; Cross Reactions; Dickeya chrysanthemi; Drug Discovery; Guinea Pigs; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 25098829
DOI: 10.1111/nyas.12496 -
Expert Opinion on Drug Discovery Dec 2016Leukemia is a collection of highly heterogeneous cancers that arise from neoplastic transformation and clonal expansion of immature hematopoietic cells. Post-treatment... (Review)
Review
Leukemia is a collection of highly heterogeneous cancers that arise from neoplastic transformation and clonal expansion of immature hematopoietic cells. Post-treatment recurrence is high, especially among elderly patients, thus necessitating more effective treatment modalities. Development of novel anti-leukemic compounds relies heavily on traditional in vitro screens which require extensive resources and time. Therefore, integration of in silico screens prior to experimental validation can improve the efficiency of pre-clinical drug development. Areas covered: This article reviews different methods and frameworks used to computationally screen for anti-leukemic agents. In particular, three approaches are discussed including molecular docking, transcriptomic integration, and network analysis. Expert opinion: Today's data deluge presents novel opportunities to develop computational tools and pipelines to screen for likely therapeutic candidates in the treatment of leukemia. Formal integration of these methodologies can accelerate and improve the efficiency of modern day anti-leukemic drug discovery and ease the economic and healthcare burden associated with it.
Topics: Animals; Antineoplastic Agents; Computer Simulation; Computer-Aided Design; Drug Design; Drug Discovery; Drug Evaluation, Preclinical; Humans; Leukemia; Molecular Docking Simulation
PubMed: 27689915
DOI: 10.1080/17460441.2016.1243524 -
Journal of Experimental & Clinical... Jul 2023The emergence of resistance to the highly successful BCL2-directed therapy is a major unmet need in acute myeloid leukemia (AML), an aggressive malignancy with poor...
INTRODUCTION
The emergence of resistance to the highly successful BCL2-directed therapy is a major unmet need in acute myeloid leukemia (AML), an aggressive malignancy with poor survival rates. Towards identifying therapeutic options for AML patients who progress on BCL2-directed therapy, we studied a clinical-stage CDK7 inhibitor XL102, which is being evaluated in solid tumors (NCT04726332).
MATERIALS AND METHODS
To determine the anti-proliferative effects of XL102, we performed experiments including time-resolved fluorescence resonance energy transfer, target occupancy, cell cycle and apoptosis-based assays. We also included genetically characterized primary myeloid blasts from de novo and relapsed/refractory AML patients. For mechanistic studies, CRISPR/Cas9 mediated knockout of CDK7 and c-Myc and immunoblotting were performed. NOD/SCID orthotropic and subcutaneous AML xenografts were used to determine anti-leukemic effects. To assess the synergistic effects of XL102 with Venetoclax, we performed RNA sequencing and gene set enrichment analysis using Venetoclax sensitive and resistant model systems.
RESULTS
XL102, a highly specific, orally bioavailable covalent inhibitor of CDK7. Inhibitory effect on CDK7 by XL102 in primary myeloid blasts (n = 54) was in nanomolar range (mean = 300 nM; range = 4.0-952 nM). XL102 treated AML cells showed a reduction in phosphorylation levels of Serine 2/5/7 at carboxy-terminal domain of RNA polymerase II. T-loop phosphorylation of CDK1(Thr161) and CDK2(Thr160) was inhibited by XL102 in dose-dependent manner leading to cell-cycle arrest. c-Myc downregulation and enhanced levels of p53 and p21 in XL102 treated cells were observed. Increased levels of p21 and activation of p53 by XL102 were mimicked by genetic ablation of CDK7, which supports that the observed effects of XL102 are due to CDK7 inhibition. XL102 treated AML xenografts showed remarkable reduction in hCD45 + marrow cells (mean = 0.60%; range = 0.04%-3.53%) compared to vehicle control (mean = 38.2%; range = 10.1%-78%), with corresponding increase in p53, p21 and decrease in c-Myc levels. The data suggests XL102 induces apoptosis in AML cells via CDK7/c-Myc/p53 axis. RNA-sequencing from paired Venetoclax-sensitive and Venetoclax-resistant cells treated with XL102 showed downregulation of genes involved in proliferation and apoptosis.
CONCLUSION
Taken together, XL102 with Venetoclax led to synergistic effects in overcoming resistance and provided a strong rationale for clinical evaluation of XL102 as a single agent and in combination with Venetoclax.
Topics: Humans; Cell Line, Tumor; Tumor Suppressor Protein p53; Leukemia, Myeloid, Acute; Apoptosis; Cyclin-Dependent Kinases; Proto-Oncogene Proteins c-bcl-2; Antineoplastic Agents
PubMed: 37507802
DOI: 10.1186/s13046-023-02750-w