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Acta Pharmacologica Sinica Jun 2024Histone deacetylase inhibitors (HDACis) are important drugs for cancer therapy, but the indistinct resistant mechanisms of solid tumor therapy greatly limit their...
Histone deacetylase inhibitors (HDACis) are important drugs for cancer therapy, but the indistinct resistant mechanisms of solid tumor therapy greatly limit their clinical application. In this study we conducted HDACi-perturbated proteomics and phosphoproteomics analyses in HDACi-sensitive and -resistant cell lines using a tandem mass tag (TMT)-based quantitative proteomic strategy. We found that the ribosome biogenesis proteins MRTO4, PES1, WDR74 and NOP16 vital to tumorigenesis might regulate the tumor sensitivity to HDACi. By integrating HDACi-perturbated protein signature with previously reported proteomics and drug sensitivity data, we predicted and validated a series of drug combination pairs potentially to enhance the sensitivity of HDACi in diverse solid tumor. Functional phosphoproteomic analysis further identified the kinase PDK1 and ROCK as potential HDACi-resistant signatures. Overall, this study reveals the potential HDACi-resistant signatures and may provide promising drug combination strategies to attenuate the resistance of solid tumor to HDACi.
Topics: Humans; Histone Deacetylase Inhibitors; Drug Resistance, Neoplasm; Proteomics; Neoplasms; Cell Line, Tumor; Antineoplastic Agents
PubMed: 38383757
DOI: 10.1038/s41401-024-01236-5 -
Current Issues in Molecular Biology Jul 2023Hepatocellular carcinoma (HCC) is a worldwide health issue. Epigenetic alterations play a crucial role in HCC tumorigenesis. Using epigenetic modulators for HCC...
The Synergistic Antitumor Effect of Decitabine and Vorinostat Combination on HepG2 Human Hepatocellular Carcinoma Cell Line via Epigenetic Modulation of Autophagy-Apoptosis Molecular Crosstalk.
Hepatocellular carcinoma (HCC) is a worldwide health issue. Epigenetic alterations play a crucial role in HCC tumorigenesis. Using epigenetic modulators for HCC treatment confers a promising therapeutic effect. The aim of this study was to explore the effect of a decitabine (DAC) and vorinostat (VOR) combination on the crosstalk between apoptosis and autophagy in the HCC HepG2 cell line at 24 h and 72 h. Median inhibitory concentrations (ICs) of VOR and DAC were assessed in the HepG2 cell line. The activity of caspase-3 was evaluated colorimetrically, and Cyclin D1(CCND1), Bcl-2, ATG5, ATG7, and P62 levels were assessed using ELISA at different time intervals (24 h and 72 h), while and gene expression were measured by using qRT-PCR. The synergistic effect of VOR and DAC was confirmed due to the observed combination indices (CIs) and dose reduction indices (DRIs). The combined treatment with both drugs inhibited the proliferation marker (CCND1), and enhanced apoptosis compared with each drug alone at 24 h and 72 h via active caspase-3 upregulation and Bcl-2 downregulation). Moreover, the combination induced autophagy as an early event via upregulation of , , ATG5, and ATG7 gene expression. The initial induction of autophagy started to decrease after 72 h due to downregulation, and there was decreased expression of compared with the value at 24 h. Herein, epigenetic modulation via the VOR/DAC combination showed an antitumor effect through the coordination of an autophagy-apoptosis crosstalk and promotion of autophagy-induced apoptosis, which ultimately led to the cellular death of HCC cancer cells.
PubMed: 37504291
DOI: 10.3390/cimb45070375 -
International Journal of Biological... 2023Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited...
Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited and the underlying mechanism remains poorly understood. Targeting histone modifications is an emerging strategy for cancer therapy, but little is known regarding the role of heat stress in altering these modifications. Here, we report that heat shock inhibits H3K9 acetylation (H3K9ac) via histone deacetylase 6 (HDAC6) regulation. Heat shock inhibits the interaction between HDAC6 and heat shock protein 90 (HSP90), enhances nuclear localization of HDAC6, and promotes HDAC6 phosphorylation, which is regulated by protein phosphatase 2A (PP2A). Combining hyperthermia with HDAC inhibitors vorinostat or panobinostat leads to better anti-cancer effects compared to monotherapy. and as genes affected by heat-induced inhibition of H3K9ac, and combining them with hyperthermia can better induce apoptosis in tumor cells. This study reveals previously unknown mechanisms of H3K9ac decreased by heat shock in cancer cells and highlights a potential combinational therapy involving hyperthermia and targeting of these new mechanisms.
Topics: Kelch-Like ECH-Associated Protein 1; Histone Deacetylases; Acetylation; Hydroxamic Acids; NF-E2-Related Factor 2; Heat-Shock Response; Hyperthermia, Induced; Neoplasms
PubMed: 37781518
DOI: 10.7150/ijbs.86384 -
Nature Communications Apr 2024Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes...
Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we find that SF3B1-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.
Topics: Humans; Splicing Factor U2AF; R-Loop Structures; Serine-Arginine Splicing Factors; RNA Splicing Factors; Myelodysplastic Syndromes; Mutation; Transcription Factors; Phosphoproteins
PubMed: 38589367
DOI: 10.1038/s41467-024-46547-7 -
Experimental Hematology & Oncology Apr 2024Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs... (Review)
Review
Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives.
Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In MM, inhibition of histone deacetylase has many downstream consequences, including suppression of NF-κB signaling and HSP90, upregulation of cell cycle regulators (p21, p53), and downregulation of antiapoptotic proteins including Bcl-2. Furthermore, HDACis have a variety of direct and indirect oxidative effects on cellular DNA. HDAC inhibitors enhance normal immune function, thereby decreasing the proliferation of malignant plasma cells and promoting autophagy. The various biological effects of inhibiting histone deacetylase have a combined or additional impact when used alongside other chemotherapeutic and targeted drugs for multiple myeloma. This helps to decrease resistance to treatment. Combination treatment regimens that include HDACis have become an essential part of the therapy for multiple myeloma. These regimens incorporate drugs from other important classes of anti-myeloma agents, such as immunomodulatory drugs (IMiDs), conventional chemotherapy, monoclonal antibodies, and proteasome inhibitors. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.
PubMed: 38654286
DOI: 10.1186/s40164-024-00507-5 -
PeerJ 2023This research aimed to ascertain the neuroprotective effect of histone deacetylase (HDAC) inhibition on retinal photoreceptors in mice, a model of retinitis pigmentosa...
PURPOSE
This research aimed to ascertain the neuroprotective effect of histone deacetylase (HDAC) inhibition on retinal photoreceptors in mice, a model of retinitis pigmentosa (RP)
METHODS
Single-cell RNA-sequencing (scRNA-seq) explored HDAC and poly (ADP-ribose) polymerase (PARP)-related gene expression in both -mutant and wild-type (WT) mice. The CUT&Tag method was employed to examine the functions of HDAC in mice. Organotypic retinal explant cultures from WT and mice were exposed to the HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) postnatally, from day 5 to day 11. The terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to quantify the percentage of photoreceptor loss in the outer nuclear layer (ONL). HDAC activity was confirmed to be inhibited by SAHA through an HDAC activity assay. Moreover, the study evaluated PARP activity, a key driver of the initial response to DNA damage during photoreceptor degeneration, following HDAC inhibition.
RESULTS
The scRNA-seq revealed that diverse roles of HDAC and PARP isoforms in photoreceptor cell death. HDAC-related genes appeared to regulate cell death and primary immunodeficiency. Alterations in HDAC activity were consistent with the TUNEL-positive cells in the ONL at different time points. Notably, SAHA significantly postponed photoreceptor loss and decreased HDAC and PARP activity, thereby implicating both in the same degenerative pathway.
CONCLUSIONS
This study highlights that the interaction between HDAC inhibition and PARP can delay photoreceptor cell death, proposing a promising therapeutic approach for RP.
Topics: Mice; Animals; Histone Deacetylases; Poly(ADP-ribose) Polymerase Inhibitors; Single-Cell Gene Expression Analysis; Retinitis Pigmentosa; Photoreceptor Cells; Poly(ADP-ribose) Polymerases; Vorinostat
PubMed: 37456870
DOI: 10.7717/peerj.15659 -
Frontiers in Cell and Developmental... 2023In 2023, approximately 288,300 new diagnoses of prostate cancer will occur, with 34,700 disease-related deaths. Death from prostate cancer is associated with metastasis,...
In 2023, approximately 288,300 new diagnoses of prostate cancer will occur, with 34,700 disease-related deaths. Death from prostate cancer is associated with metastasis, enabled by progression of tumor phenotypes and successful extracapsular extension to reach Batson's venous plexus, a specific route to the spine and brain. Using a mouse-human tumor xenograft model, we isolated an aggressive muscle invasive cell population of prostate cancer, called DU145 with a distinct biophysical phenotype, elevated histone H3K27, and increased matrix metalloproteinase 14 expression as compared to the non-aggressive parent cell population called DU145. Our goal was to determine the sensitivities to known chemotherapeutic agents of the aggressive cells as compared to the parent population. High-throughput screening was performed with 5,578 compounds, comprising of approved and investigational drugs for oncology. Eleven compounds were selected for additional testing, which revealed that vorinostat, 5-azacitidine, and fimepinostat (epigenetic inhibitors) showed 2.6-to-7.5-fold increases in lethality for the aggressive prostate cancer cell population as compared to the parent, as judged by the concentration of drug to inhibit 50% cell growth (IC). On the other hand, the DU145 cells were 2.2-to-4.0-fold resistant to mitoxantrone, daunorubicin, and gimatecan (topoisomerase inhibitors) as compared to DU145. No differences in sensitivities between cell populations were found for docetaxel or pirarubicin. The increased sensitivity of DU145 prostate cancer cells to chromatin modifying agents suggests a therapeutic vulnerability occurs after tumor cells invade into and through muscle. Future work will determine which epigenetic modifiers and what combinations will be most effective to eradicate early aggressive tumor populations.
PubMed: 38046670
DOI: 10.3389/fcell.2023.1285372 -
Radiotherapy and Oncology : Journal of... Nov 2023Patterns of failure (POF) may provide an alternative quantitative endpoint to overall survival for evaluation of novel chemoradiotherapy regimens with glioblastoma.
BACKGROUND
Patterns of failure (POF) may provide an alternative quantitative endpoint to overall survival for evaluation of novel chemoradiotherapy regimens with glioblastoma.
MATERIALS AND METHODS
POF of 109 newly-diagnosed glioblastoma patients per 2016 WHO classification who received conformal radiotherapy with concomitant and adjuvant temozolomide were reviewed. Seventy-five of those patients also received an investigational chemotherapy agent (everolimus, erlotinib, or vorinostat). Recurrence volumes were defined with MRI contrast enhancement. POF at protocol (POF), initial (POF), and RANO (POF) progression timepoints were characterized by the percentage of recurrence volume within the 95% dose region. POF, POF, and POF of each patient were categorized (central, non-central, or both).
RESULTS
POF of the temozolomide-only control cohort were unchanged (79% central, 12% non-central, and 9% both) across protocol, initial, and RANO progression timepoints. Unlike the temozolomide-only cohort, POF of the collective novel chemotherapy cohort appeared increasingly non-central when comparing POF with POF, with a non-central component increasing from 16% to 29% (p = 0.078). POF did not correlate with overall survival or time to progression.
CONCLUSION
POF of patients receiving a novel chemotherapy appeared to be influenced by the timepoint of analysis and were increasingly non-central at protocol progression as compared with initial recurrence, suggesting that recurrence originates from the central region. Addition of everolimus and vorinostat appeared to influence POF, despite similar survival outcomes with the temozolomide-only control group. In studies dealing with novel therapeutic agents, robust and properly-timed dosimetric POF analysis may be helpful to evaluate biologic aspects of novel agents.
PubMed: 37385378
DOI: 10.1016/j.radonc.2023.109768 -
Biomedical Reports Jul 2024Previously, we demonstrated that cationic liposomes comprised of -hexadecyl-,-dimethylhexadecan-1-aminium bromide, 1,2-dioleoyl--glycero-3-phosphoethanolamine and...
Previously, we demonstrated that cationic liposomes comprised of -hexadecyl-,-dimethylhexadecan-1-aminium bromide, 1,2-dioleoyl--glycero-3-phosphoethanolamine and poly(ethylene glycol) cholesteryl ether induced substantial protein expression both and following the administration of mRNA/cationic liposome complexes (mRNA lipoplexes). The present study evaluated the effect of vorinostat, a histone deacetylase inhibitor, on protein expression levels and following the administration of mRNA lipoplexes. The half-maximal inhibitory concentration (IC) values of vorinostat for human cervical carcinoma HeLa and human liver cancer HepG2 cells were determined to be 7.8 and 2.6 µM, respectively, following a 24 h incubation period. Treatment with 1 µM vorinostat resulted in a 2.7-fold increase in luciferase (Luc) activity for HeLa cells and a 1.6-fold increase for HepG2 cells at 24 h post-transfection with Luc (FLuc) mRNA lipoplexes compared with untreated cells. However, treatment with 10 µM vorinostat decreased Luc activity compared with treatment with 1 µM vorinostat. Intravenous injection of Cy5-labeled mRNA lipoplexes into mice resulted in mRNA accumulation primarily in the lungs; however, co-injection with vorinostat at doses of 5 or 25 mg/kg resulted in mRNA accumulation in both the lungs and liver. Furthermore, intravenous injection of FLuc mRNA lipoplexes resulted in high Luc activity in both the lungs and spleen. Nevertheless, co-injection with vorinostat slightly decreased Luc activity in the lungs but not in the spleen. These findings indicated that vorinostat enhances protein expression from transfected mRNA after treatment with a lower concentration of IC; however, it does not largely affect protein expression from the transfected mRNA.
PubMed: 38868527
DOI: 10.3892/br.2024.1793 -
Daru : Journal of Faculty of Pharmacy,... Jun 2024Identifying the molecular mechanisms behind SARS-CoV-2 disparities and similarities will help find new treatments. The present study determines networks' shared and...
Deciphering the similarities and disparities of molecular mechanisms behind respiratory epithelium response to HCoV-229E and SARS-CoV-2 and drug repurposing, a systems biology approach.
PURPOSE
Identifying the molecular mechanisms behind SARS-CoV-2 disparities and similarities will help find new treatments. The present study determines networks' shared and non-shared (specific) crucial elements in response to HCoV-229E and SARS-CoV-2 viruses to recommend candidate medications.
METHODS
We retrieved the omics data on respiratory cells infected with HCoV-229E and SARS-CoV-2, constructed PPIN and GRN, and detected clusters and motifs. Using a drug-gene interaction network, we determined the similarities and disparities of mechanisms behind their host response and drug-repurposed.
RESULTS
CXCL1, KLHL21, SMAD3, HIF1A, and STAT1 were the shared DEGs between both viruses' protein-protein interaction network (PPIN) and gene regulatory network (GRN). The NPM1 was a specific critical node for HCoV-229E and was a Hub-Bottleneck shared between PPI and GRN in HCoV-229E. The HLA-F, ADCY5, TRIM14, RPF1, and FGA were the seed proteins in subnetworks of the SARS-CoV-2 PPI network, and HSPA1A and RPL26 proteins were the seed in subnetworks of the PPI network of HCOV-229E. TRIM14, STAT2, and HLA-F played the same role for SARS-CoV-2. Top enriched KEGG pathways included cell cycle and proteasome in HCoV-229E and RIG-I-like receptor, Chemokine, Cytokine-cytokine, NOD-like receptor, and TNF signaling pathways in SARS-CoV-2. We suggest some candidate medications for COVID-19 patient lungs, including Noscapine, Isoetharine mesylate, Cycloserine, Ethamsylate, Cetylpyridinium, Tretinoin, Ixazomib, Vorinostat, Venetoclax, Vorinostat, Ixazomib, Venetoclax, and epoetin alfa for further in-vitro and in-vivo investigations.
CONCLUSION
We suggested CXCL1, KLHL21, SMAD3, HIF1A, and STAT1, ADCY5, TRIM14, RPF1, and FGA, STAT2, and HLA-F as critical genes and Cetylpyridinium, Cycloserine, Noscapine, Ethamsylate, Epoetin alfa, Isoetharine mesylate, Ribavirin, and Tretinoin drugs to study further their importance in treating COVID-19 lung complications.
Topics: Humans; Drug Repositioning; SARS-CoV-2; Protein Interaction Maps; Systems Biology; Coronavirus 229E, Human; Antiviral Agents; COVID-19 Drug Treatment; Nucleophosmin; Respiratory Mucosa; Gene Regulatory Networks; COVID-19
PubMed: 38652363
DOI: 10.1007/s40199-024-00507-0