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3 Biotech Mar 2024Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected...
Discovery of novel anticancer flavonoids as potential HDAC2 inhibitors: virtual screening approach based on molecular docking, DFT and molecular dynamics simulations studies.
UNLABELLED
Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO-LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-023-03912-5.
PubMed: 38375511
DOI: 10.1007/s13205-023-03912-5 -
Biochemical Pharmacology Feb 2024The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half...
The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.
PubMed: 38373594
DOI: 10.1016/j.bcp.2024.116065 -
Cell Feb 2024CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection.... (Randomized Controlled Trial)
Randomized Controlled Trial
CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.
Topics: Humans; HIV Infections; HIV-1; Panobinostat; Proviruses; Virus Latency; Histone Deacetylase Inhibitors; Interferon-alpha
PubMed: 38367616
DOI: 10.1016/j.cell.2024.01.037 -
Heart, Lung & Circulation May 2024Increased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular...
BACKGROUND
Increased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular (CV) damage, significantly threatening the health and quality of life of patients living with, through and beyond cancer. Without understanding the mechanisms, including whether the cardiotoxicity is due to the direct or indirect effects on cardiomyocytes, prevention and management of cardiotoxicity can pose challenges in many patients. To date, the cardiotoxicity profiles of most of the chemotherapy drugs are still poorly understood.
AIM
To conduct a pilot study to investigate the direct effects of a range of cancer therapies on cardiomyocyte viability.
METHODS
Primary human cardiomyocytes (HCM) were cultured and seeded into 96-well culture plates. A total of 35 different Food and Drug Administration-approved anti-cancer drugs were added to the HCM cells with a concentration of 1uM for 72 hours. The viability of HCMs was determined using CellTitre-Glo. The experiments were repeated at least three times for each drug with HCMs of different passages.
RESULTS
We identified 15 anti-cancer agents that significantly reduced HCM viability. These drugs were: (1) anthracyclines (daunorubicin [HCM viability, mean %±standard error, 13.7±3.2%], epirubicin [47.6±5.3%]), (2) antimetabolite (azacitidine [67.1±2.4%]), (3) taxanes (paclitaxel [60.2±3.0%]), (4) protein kinase inhibitors (lapatinib [49.8±7.0%], ponatinib [42.4±9.0%], pemigatinib [68.1±2.3%], sorafenib [52.9±10.6%], nilotinib [64.4±4.5%], dasatinib [38.5±3.6%]), (5) proteasome inhibitors (ixazomib citrate [65.4±7.2%]), (6) non-selective histone-deacetylase inhibitor (panobinostat [19.1±4.1%]), poly adenosine diphosphate-ribose polymerase inhibitor (olaparib [68.2±1.7%]) and (7) vinca alkaloids (vincristine [44.6±7.4%], vinblastine [31.2±3.9%]).
CONCLUSIONS
In total, 15 of the 35 commercially available anti-cancer drugs have direct cardiotoxic effects on HCM. Some of those, have not been associated with clinical cardiotoxicity, while others, known to be cardiotoxic do not appear to mediate it via direct effects on cardiomyocytes. More detailed investigations of the effects of cancer therapies on various cardiovascular cells should be performed to comprehensively determine the mechanisms of cardiotoxicity.
Topics: Humans; Myocytes, Cardiac; Antineoplastic Agents; Cell Survival; Cardiotoxicity; Neoplasms; Cells, Cultured; Pilot Projects; Female
PubMed: 38365500
DOI: 10.1016/j.hlc.2024.01.013 -
Cells Jan 2024Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and...
Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.
Topics: Animals; Mice; Histone Deacetylase Inhibitors; Histones; Glioma; Benzamides; Biphenyl Compounds; Morpholines; Pyridones
PubMed: 38334611
DOI: 10.3390/cells13030219 -
Archives of Iranian Medicine Sep 2023Several studies have revealed that the aberrant expressions of forkhead box (FOX) genes are associated with carcinogenesis. However, the crucial biological functions of...
BACKGROUND
Several studies have revealed that the aberrant expressions of forkhead box (FOX) genes are associated with carcinogenesis. However, the crucial biological functions of the FOX gene in colon adenocarcinoma (COAD) remain unknown.
METHODS
The TCGA-COAD dataset (n=328) was utilized for determining the deregulated FOX genes and their association with functional enrichment, protein-protein interaction (PPI), survival prognosis, anti-tumor immunity, cancer-associated pathways, and biological processes in COAD. In addition, we used GSE166427 (GPL13667) as a validation cohort (n=196). Molecular docking studies were applied to perform the drug interactions.
RESULTS
The FOX genes are deregulated in the COAD (Log FC>0.50, <0.05), and the PPI network of FOX members is substantially related to the enrichment of cancerous signaling, immune responses, and cellular development (FDR<0.05). A worse prognosis for overall survival in COAD individuals is connected with the subgroup of FOX transcripts (≤0.05). , , and were identified as predictive variables in the univariate and multivariate Cox regression models (≤0.05). and are substantially linked to the deregulated immunity in COAD (R>0.20, <0.01). Furthermore, expression regulates cancer-associated pathways and biological processes (<0.05). Moreover, , , and are genetically altered and showed diagnostic efficacy in COAD. We revealed that , , and are consistently deregulated in GSE166427 (<0.05). Finally, molecular docking revealed that interacted with various drugs, including belinostat, entinostat, and panobinostat.
CONCLUSION
The FOX genes have a strong correlation with the poor prognosis for survival, tumor immunity, cancer-associated pathways, and biochemical processes that cause the pathogenesis of COAD.
Topics: Humans; Colonic Neoplasms; Adenocarcinoma; Molecular Docking Simulation; Prognosis; Carcinogenesis; Forkhead Transcription Factors
PubMed: 38310407
DOI: 10.34172/aim.2023.77 -
Genome Research Feb 2024Histone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of...
Histone acetylation is a dynamic modification regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Deacetylation of histone tails results in chromatin tightening, and therefore, HDACs are generally regarded as transcriptional repressors. Counterintuitively, simultaneous deletion of and in embryonic stem cells (ESCs) reduces expression of the pluripotency-associated transcription factors , , and (PSN). By shaping global histone acetylation patterns, HDACs indirectly regulate the activity of acetyl-lysine readers, such as the transcriptional activator BRD4. Here, we use inhibitors of HDACs and BRD4 (LBH589 and JQ1, respectively) in combination with precision nuclear run-on and sequencing (PRO-seq) to examine their roles in defining the ESC transcriptome. Both LBH589 and JQ1 cause a marked reduction in the pluripotent gene network. However, although JQ1 treatment induces widespread transcriptional pausing, HDAC inhibition causes a reduction in both paused and elongating polymerase, suggesting an overall reduction in polymerase recruitment. Using enhancer RNA (eRNA) expression to measure enhancer activity, we find that LBH589-sensitive eRNAs are preferentially associated with superenhancers and PSN binding sites. These findings suggest that HDAC activity is required to maintain pluripotency by regulating the PSN enhancer network via the recruitment of RNA polymerase II.
Topics: Histones; Transcription Factors; RNA Polymerase II; Nuclear Proteins; Histone Deacetylases; Gene Regulatory Networks; Panobinostat; Histone Acetyltransferases; Acetylation; Histone Deacetylase Inhibitors
PubMed: 38290976
DOI: 10.1101/gr.278050.123 -
International Journal of Molecular... Jan 2024Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed...
Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
Topics: Animals; Female; Humans; Mice; Apoptosis; Cell Line, Tumor; Endometrial Neoplasms; Histone Deacetylase Inhibitors; Panobinostat; Phosphatidylinositol 3-Kinases; Molecular Targeted Therapy; Receptor, EphA2
PubMed: 38279277
DOI: 10.3390/ijms25021278 -
Journal of Hepatology Apr 2024Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new...
BACKGROUND & AIMS
Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition.
METHODS
RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen.
RESULTS
HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC of 0.013-0.059 μM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups.
CONCLUSIONS
Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB.
IMPACT AND IMPLICATIONS
Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.
Topics: Humans; Mice; Animals; Panobinostat; Hepatoblastoma; Irinotecan; Vincristine; Neoplasm Recurrence, Local; Histone Deacetylase Inhibitors; Liver Neoplasms; Hydroxamic Acids
PubMed: 38242326
DOI: 10.1016/j.jhep.2024.01.003 -
Journal of Chemical Information and... Feb 2024Ovarian cancer (OC) is a highly heterogeneous disease, with patients at different tumor staging having different survival times. Metabolic reprogramming is one of the...
Ovarian cancer (OC) is a highly heterogeneous disease, with patients at different tumor staging having different survival times. Metabolic reprogramming is one of the key hallmarks of cancer; however, the significance of metabolism-related genes in the prognosis and therapy outcomes of OC is unclear. In this study, we used weighted gene coexpression network analysis and differential expression analysis to screen for metabolism-related genes associated with tumor staging. We constructed the metabolism-related gene prognostic index (MRGPI), which demonstrated a stable prognostic value across multiple clinical trial end points and multiple validation cohorts. The MRGPI population had its distinct molecular features, mutational characteristics, and immune phenotypes. In addition, we investigated the response to immunotherapy in MRGPI subgroups and found that patients with low MRGPI were prone to benefit from anti-PD-1 checkpoint blockade therapy and exhibited a delayed treatment effect. Meanwhile, we identified four candidate therapeutic drugs (ABT-737, crizotinib, panobinostat, and regorafenib) for patients with high MRGPI, and we evaluated the pharmacokinetics and safety of the candidate drugs. In summary, the MRGPI was a robust clinical feature that could predict patient prognosis, immunotherapy response, and candidate drugs, facilitating clinical decision making and therapeutic strategy of OC.
Topics: Humans; Female; Prognosis; Immunotherapy; Ovarian Neoplasms; Metabolic Reprogramming; Mutation
PubMed: 38238993
DOI: 10.1021/acs.jcim.3c01473