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Medicine and Science in Sports and... Jun 2019The late effects of radiation therapy can have significant consequences for the health and quality of life of long-term cancer survivors. Radiation induces persistent...
INTRODUCTION
The late effects of radiation therapy can have significant consequences for the health and quality of life of long-term cancer survivors. Radiation induces persistent alterations in hematopoietic stem and progenitor cells (HSPC) and the bone marrow environment; however, how relevant host factors such as obesity and exercise differentially regulate HSPC content and the bone marrow environment after radiation exposure remains unknown. The purpose of this investigation was to evaluate how the combination of obesity and exercise training modulates HSPC and their niche after sublethal radiation exposure in mice.
METHODS
Mice fed either a control or a high-fat diet to induce obesity remained sedentary or underwent a progressive treadmill exercise program. At 13 wk of age, mice were irradiated (3 Gy) and continued their specific diets and exercise program for four more weeks.
RESULTS
Exercise-trained mice had significantly higher quantities of several HSPC subpopulations and bone marrow stromal cell populations, whereas HSPC subpopulations were significantly lower in obese mice after radiation. Reactive oxygen species content was significantly decreased in HSPC with exercise training. Proteomics analysis of bone marrow supernatant revealed clustering of biologically relevant changes in exercise-trained mice. Functional evaluation of bone marrow supernatant revealed a significant increase in leukemia blast viability in obese mice but not in the exercise-trained mice (P < 0.05).
CONCLUSION
Together, these data suggest that exercise training partially restores the negative effects of obesity on HSPC and their niche after radiation exposure. As such, exercise training should be considered to mitigate the late effects of radiation therapy on the hematopoietic system for cancer survivors with or without obesity who have undergone radiation therapy.
Topics: Animals; Bone Marrow Cells; Cell Survival; Cytokines; Granulocyte Precursor Cells; Hematopoiesis; Hematopoietic Stem Cells; Leukemia; Male; Mice, Inbred CBA; Obesity; Oxidative Stress; Physical Conditioning, Animal; Whole-Body Irradiation
PubMed: 30640286
DOI: 10.1249/MSS.0000000000001894 -
Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells.Anticancer Research Sep 2021Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to...
BACKGROUND/AIM
Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs.
MATERIALS AND METHODS
Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells.
RESULTS
HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax.
CONCLUSION
HL60/VEN cells exhibited up-regulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.
Topics: ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Sulfonamides; Up-Regulation
PubMed: 34475043
DOI: 10.21873/anticanres.15228 -
International Journal of Molecular... Dec 2023Chalcones and their derivatives, both natural and synthetic, exhibit diverse biological activities. In this study, we focused on designing and synthesizing...
Chalcones and their derivatives, both natural and synthetic, exhibit diverse biological activities. In this study, we focused on designing and synthesizing ()-2,4-dichloro--(4-cinnamoylphenyl)-5-methylbenzenesulfonamides - with the following two pharmacophore groups: 2,4-dichlorobenzenesulfonamide and chalcone. The obtained compounds displayed notable anticancer effects on various human cancer cells, such as cervical HeLa, acute promyelocytic leukemia HL-60, and gastric adenocarcinoma AGS, when assessed with the MTT test. The activity of all compounds against cancer cells was significant, and the obtained IC values were in the range of 0.89-9.63 µg/mL. Among all the tested compounds, derivative showed the highest activity on the AGS cell line. Therefore, it was tested for cell cycle inhibition, induction of mitochondrial membrane depolarization, and activation of caspase-8 and -9. These results showed that this compound strongly arrested the cell cycle in the subG0 phase, depolarized the mitochondrial membrane, and activated caspase-8 and -9. Similar to the anticancer effects, all the obtained compounds were also assessed for their antioxidant activity. The highest antiradical effect was demonstrated for derivative , which was able to inhibit DPPH and ABTS radicals. All examined compounds showed dose-dependent activity against neutrophil elastase. Notably, derivatives and demonstrated inhibitory properties similar to oleanolic acid, with IC values of 25.61 ± 0.58 and 25.73 ± 0.39 µg/mL, respectively. To determine the antibacterial activity of derivatives -, the minimum bacteriostatic concentration (MIC) values were estimated (>500 µg/mL for all the tested bacterial strains). The findings demonstrate the substantial potential of sulfonamide-based chalcone as a promising drug in anticancer therapy.
Topics: Humans; Chalcone; Chalcones; Antioxidants; Caspase 8; HL-60 Cells
PubMed: 38203445
DOI: 10.3390/ijms25010274 -
Scientific Reports Sep 2019Identification of primary targets associated with phenotypes can facilitate exploration of the underlying molecular mechanisms of compounds and optimization of the...
Identification of primary targets associated with phenotypes can facilitate exploration of the underlying molecular mechanisms of compounds and optimization of the structures of promising drugs. However, the literature reports limited effort to identify the target major isoform of a single known target gene. The majority of genes generate multiple transcripts that are translated into proteins that may carry out distinct and even opposing biological functions through alternative splicing. In addition, isoform expression is dynamic and varies depending on the developmental stage and cell type. To identify target major isoforms, we integrated a breast cancer type-specific isoform coexpression network with gene perturbation signatures in the MCF7 cell line in the Connectivity Map database using the 'shortest path' drug target prioritization method. We used a leukemia cancer network and differential expression data for drugs in the HL-60 cell line to test the robustness of the detection algorithm for target major isoforms. We further analyzed the properties of target major isoforms for each multi-isoform gene using pharmacogenomic datasets, proteomic data and the principal isoforms defined by the APPRIS and STRING datasets. Then, we tested our predictions for the most promising target major protein isoforms of DNMT1, MGEA5 and P4HB4 based on expression data and topological features in the coexpression network. Interestingly, these isoforms are not annotated as principal isoforms in APPRIS. Lastly, we tested the affinity of the target major isoform of MGEA5 for streptozocin through in silico docking. Our findings will pave the way for more effective and targeted therapies via studies of drug targets at the isoform level.
Topics: Algorithms; Breast Neoplasms; Computer Simulation; Drug Development; Drug Discovery; Female; Gene Regulatory Networks; HL-60 Cells; Humans; MCF-7 Cells; Molecular Docking Simulation; Protein Isoforms; Proteomics
PubMed: 31554914
DOI: 10.1038/s41598-019-50224-x -
Toxicology and Applied Pharmacology Oct 2023Modern toxicology's throughput has dramatically increased due to alternative models, laboratory automation, and machine learning. This has enabled comparative studies...
Modern toxicology's throughput has dramatically increased due to alternative models, laboratory automation, and machine learning. This has enabled comparative studies across species and assays to prioritize chemical hazard potential and to understand how different model systems might complement one another. However, such comparative studies of high-throughput data are still in their infancy, with more groundwork needed to firmly establish the approach. Therefore, this study aimed to compare the bioactivity of the NIEHS Division of Translational Toxicology's (DTT) 87-compound developmental neurotoxicant (DNT) library in zebrafish and an in vitro high-throughput cell culture system. The early life-stage zebrafish provided a whole animal approach to developmental toxicity assessment. Chemical hits for abnormalities in embryonic zebrafish morphology, mortality, and behavior (ZBEscreen™) were compared with chemicals classified as high-risk by the Cell Health Index (CHI™), which is an outcome class probability from a machine learning classifier using 12 parameters from the SYSTEMETRIC® Cell Health Screen (CHS). The CHS was developed to assess human toxicity risk using supervised machine learning to classify acute cell stress phenotypes in a human leukemia cell line (HL60 cells) following a 4-h exposure to a chemical of interest. Due to the design of the screen, the zebrafish assays were more exhaustive, yielding 86 total bioactive hits, whereas the SYSTEMETRIC® CHS focusing on acute toxicity identified 20 chemicals as potentially toxic. The zebrafish embryonic and larval photomotor response assays (EPR and LPR, respectively) detected 40 of the 47 chemicals not found by the zebrafish morphological screen and CHS. Collectively, these results illustrate the advantages of using two alternative models in tandem for rapid hazard assessment and chemical prioritization and the effectiveness of CHI™ in identifying toxicity within a single multiparametric assay.
Topics: Animals; Humans; Zebrafish; Biological Assay; HL-60 Cells; Larva; Leukemia
PubMed: 37604412
DOI: 10.1016/j.taap.2023.116659 -
Cellular Signalling May 2020The promyelocytic leukemia-retinoic acid receptor α (PML/RARα) is hypothesized to play a vital role in the pathogenesis of acute promyelocytic leukemia (APL). A...
The promyelocytic leukemia-retinoic acid receptor α (PML/RARα) is hypothesized to play a vital role in the pathogenesis of acute promyelocytic leukemia (APL). A previous study has demonstrated that PML/RARα is cleaved by neutrophil elastase (NE) in early myeloid cells, which leads to an increase in the nuclear localization signal (NLS) in RARα and in the incidence of APL. In this study, we explored the effects of NLS-RARα on acute myeloid leukemia (AML) cells and studied the mechanism of its localization. LV-NLS-RARα recombinant lentivirus and negative control LV-NC lentivirus were transfected into HL-60 cells and U937 cells while mutant NLS-RARα were transfected into U937 cells, and all groups were treated with 1α, 25-dihydroxyvitamin D3(1,25D3). The results showed that NLS-RARα was located mainly in the nucleus while mutant NLS-RARα was located in the cytoplasm. Overexpression of NLS-RARα downregulated the expression of CD11b, CD11c, CD14, and three forms of CEBPβ compared to the overexpression of NC and mutant NLS-RARα. It was speculated that the abnormal localization of NLS-RARα was mediated via importin-α/β in the pathogenesis of APL. By producing point mutations in the two NLSs in NLS-RARα, we showed that the nuclear import of NLS-RARα was mainly dependent on the NLS of the RARα portion. Subsequently, we found that importin-α1 (KPNA2)/importin-β1 (KPNB1) participates in the nuclear transport of NLS-RARα. Taken together, abnormal localization of NLS-RARα blocks the differentiation of APL cells, and nuclear localization of NLS-RARα depends on NLS of the RARα portion and is mediated via binding with importin-α/β.
Topics: Active Transport, Cell Nucleus; Cell Nucleus; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Nuclear Localization Signals; Retinoic Acid Receptor alpha; U937 Cells; alpha Karyopherins; beta Karyopherins
PubMed: 32036017
DOI: 10.1016/j.cellsig.2020.109567 -
Toxins Apr 2022Cry41Aa, also called parasporin-3, belongs to a group of toxins from the entomopathogenic bacterium that show activity against human cancer cells. Cry41Aa exhibits...
Cry41Aa, also called parasporin-3, belongs to a group of toxins from the entomopathogenic bacterium that show activity against human cancer cells. Cry41Aa exhibits preferential cytocidal activity towards HL-60 (human promyelocytic leukaemia cells) and HepG2 (human liver cancer cells) cell lines after being proteolytically activated. To better understand the mechanism of action of Cry41Aa, we evolved resistance in HepG2 cells through repeated exposure to increasing doses of the toxin. Concentrations of Cry41Aa that killed over 50% of the parental HepG2 cells had no significant effect on the viability of the resistant cells and did not induce either pore formation or p38 phosphorylation (both characteristic features of pore-forming toxins). Preliminary RNA sequencing data identified AQP9 as a potential mediator of resistance, but extensive investigations failed to show a causal link and did not support an enhanced cell repair process as the resistance mechanism.
Topics: Bacillus thuringiensis; Bacterial Proteins; HL-60 Cells; Hep G2 Cells; Humans
PubMed: 35622566
DOI: 10.3390/toxins14050319 -
Journal of Nippon Medical School =... Mar 2021Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical...
BACKGROUND
Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is needed.
METHODS
This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 10 CD34-positive cells/kg (range: 0.3-47.4 × 10 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 10 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed.
RESULTS
The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 [72.3%] vs. n = 11 [44.0%] in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 10/μL; range: 1.60-47.4 × 10 cells/μL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment.
CONCLUSION
The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.
Topics: Adolescent; Adult; Aged; Antigens, CD34; Female; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Lymphoma; Male; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Peripheral Blood Stem Cells; Retrospective Studies; Time Factors; Tissue and Organ Harvesting; Transplantation, Autologous; Young Adult
PubMed: 32238739
DOI: 10.1272/jnms.JNMS.2021_88-104 -
The Science of the Total Environment Apr 2023The cellular and molecular mechanisms by which atmospheric pollution from particulate matter and/or electromagnetic fields (EMFs) may prove harmful to human health have...
The HL-60 human promyelocytic cell line constitutes an effective in vitro model for evaluating toxicity, oxidative stress and necrosis/apoptosis after exposure to black carbon particles and 2.45 GHz radio frequency.
The cellular and molecular mechanisms by which atmospheric pollution from particulate matter and/or electromagnetic fields (EMFs) may prove harmful to human health have not been extensively researched. We analyzed whether the combined action of EMFs and black carbon (BC) particles induced cell damage and a pro-apoptotic response in the HL-60 promyelocytic cell line when exposed to 2.45 GHz radio frequency (RF) radiation in a gigahertz transverse electromagnetic (GTEM) chamber at sub-thermal specific absorption rate (SAR) levels. RF and BC induced moderately significant levels of cell damage in the first 8 or 24 h for all exposure times/doses and much greater damage after 48 h irradiation and the higher dose of BC. We observed a clear antiproliferative effect that increased with RF exposure time and BC dose. Oxidative stress or ROS production increased with time (24 or 48 h of radiation), BC dose and the combination of both. Significant differences between the proportion of damaged and healthy cells were observed in all groups. Both radiation and BC participated separately and jointly in triggering necrosis and apoptosis in a programmed way. Oxidative-antioxidant action activated mitochondrial anti-apoptotic BCL2a gene expression after 24 h irradiation and exposure to BC. After irradiation of the cells for 48 h, expression of FASR cell death receptors was activated, precipitating the onset of pro-apoptotic phenomena and expression and intracellular activity of caspase-3 in the mitochondrial pathways, all of which can lead to cell death. Our results indicate that the interaction between BC and RF modifies the immune response in the human promyelocytic cell line and that these cells had two fates mediated by different pathways: necrosis and mitochondria-caspase dependent apoptosis. The findings may be important in regard to antimicrobial, inflammatory and autoimmune responses in humans.
Topics: Humans; HL-60 Cells; Apoptosis; Necrosis; Radio Waves; Oxidative Stress; Carbon; Electromagnetic Fields
PubMed: 36632900
DOI: 10.1016/j.scitotenv.2023.161475 -
European Journal of Medicinal Chemistry Mar 2023Salinomycin (SAL) is a natural polyether ionophore that exhibits a very broad spectrum of biological effects, ranging from anticancer to antiparasitic activities. Our...
Salinomycin (SAL) is a natural polyether ionophore that exhibits a very broad spectrum of biological effects, ranging from anticancer to antiparasitic activities. Our recent studies have shown that the chemical modification of the SAL biomolecule is a fruitful strategy for generating lead compounds for the development of novel antitrypanosomal agents. As a continuation of our program to develop trypanocidal active lead structures, we synthesized a series of 14 novel urea and thiourea analogs of C20-epi-aminosalinomycin (compound 2b). The trypanocidal and cytotoxic activities of the derivatives were assessed with the mammalian life cycle stage of Trypanosoma brucei and human leukemic HL-60 cells, respectively. The most antitrypanosomal compounds were the two thiourea derivatives 4b (C20-n-butylthiourea) and 4d (C20-phenylthiourea) with 50% growth inhibition (GI) values of 0.18 and 0.22 μM and selectivity indices of 47 and 41, respectively. As potent SAL derivatives have been shown to induce strong cell swelling in bloodstream forms of T. brucei, the effect of compounds 4b and 4d to increase the cell volume of the parasite was also investigated. Interestingly, both derivatives were capable to induce faster cell swelling in bloodstream-form trypanosomes than the reference compound SAL. These findings support the suggestion that C20-epi-aminosalinomycin derivatives are suitable leads in the rational development of new and improved trypanocidal drugs.
Topics: Animals; Humans; Trypanosoma brucei brucei; Urea; Trypanocidal Agents; HL-60 Cells; Thiourea; Mammals
PubMed: 36870272
DOI: 10.1016/j.ejmech.2023.115241