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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 -
Life Sciences Dec 2023The aim of our study was to determine the effect of histone deacetylase (HDAC) inhibitors (HDACis) on somatostatin type-2 receptor (SSTR2) expression and...
AIMS
The aim of our study was to determine the effect of histone deacetylase (HDAC) inhibitors (HDACis) on somatostatin type-2 receptor (SSTR2) expression and [In]In-/[Lu]Lu-DOTA-TATE uptake in vitro and in vivo.
MATERIALS AND METHODS
The human cell lines NCI-H69 (small-cell lung carcinoma) and BON-1 (pancreatic neuroendocrine tumor) were treated with HDACis (i.e. entinostat, mocetinostat (MOC), LMK-235, CI-994 or panobinostat (PAN)), and SSTR2 mRNA expression levels and [In]In-DOTA-TATE uptake were measured. Furthermore, vehicle- and HDACi-treated NCI-H69 and BON-1 tumor-bearing mice were injected with radiolabeled DOTA-TATE followed by biodistribution studies. Additionally, SSTR2 and HDAC mRNA expression of xenografts, and of NCI-H69, BON-1, NCI-H727 (human pulmonary carcinoid) and GOT1 (human midgut neuroendocrine tumor) cells were determined.
KEY FINDINGS
HDACi treatment resulted in the desired effects in vitro. However, no significant increase in tumoral DOTA-TATE uptake was observed after HDACi treatment in NCI-H69 tumor-bearing animals, whereas tumoral SSTR2 mRNA and/or protein expression levels were significantly upregulated after treatment with MOC, CI-994 and PAN, i.e. a maximum of 2.1- and 1.3-fold, respectively. Analysis of PAN-treated BON-1 xenografts solely demonstrated increased SSTR2 mRNA expression levels. Comparison of HDACs and SSTR2 expression in BON-1 and NCI-H69 xenografts showed a significantly higher expression of 6/11 HDACs in BON-1 xenografts. Of these HDACs, a significant inverse correlation was found between HDAC3 and SSTR2 expression (Pearson r = -0.92) in the studied cell lines.
SIGNIFICANCE
To conclude, tumoral uptake levels of radiolabeled DOTA-TATE were not enhanced after HDACi treatment in vivo, but, depending on the applied inhibitor, increased SSTR2 expression levels were observed.
Topics: Humans; Mice; Animals; Receptors, Somatostatin; Tissue Distribution; Somatostatin; Cell Line, Tumor; RNA, Messenger
PubMed: 37907154
DOI: 10.1016/j.lfs.2023.122173 -
Nature Methods Nov 2023Understanding and predicting molecular responses in single cells upon chemical, genetic or mechanical perturbations is a core question in biology. Obtaining single-cell...
Understanding and predicting molecular responses in single cells upon chemical, genetic or mechanical perturbations is a core question in biology. Obtaining single-cell measurements typically requires the cells to be destroyed. This makes learning heterogeneous perturbation responses challenging as we only observe unpaired distributions of perturbed or non-perturbed cells. Here we leverage the theory of optimal transport and the recent advent of input convex neural architectures to present CellOT, a framework for learning the response of individual cells to a given perturbation by mapping these unpaired distributions. CellOT outperforms current methods at predicting single-cell drug responses, as profiled by scRNA-seq and a multiplexed protein-imaging technology. Further, we illustrate that CellOT generalizes well on unseen settings by (1) predicting the scRNA-seq responses of holdout patients with lupus exposed to interferon-β and patients with glioblastoma to panobinostat; (2) inferring lipopolysaccharide responses across different species; and (3) modeling the hematopoietic developmental trajectories of different subpopulations.
Topics: Humans; Single-Cell Analysis; Sequence Analysis, RNA; Gene Expression Profiling
PubMed: 37770709
DOI: 10.1038/s41592-023-01969-x -
Hematology (Amsterdam, Netherlands) Dec 2023Although multiple myeloma is still incurable, an abundance of novel treatments have become available for relapsed and or refractory multiple myeloma (RRMM). Direct... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although multiple myeloma is still incurable, an abundance of novel treatments have become available for relapsed and or refractory multiple myeloma (RRMM). Direct head-to-head comparisons between the novel treatments are lacking. We performed a network meta-analysis to evaluate immediate effects such as response quality of current novel-drugs combined therapeutic regimens, with the aim to identify treatments that could be more effective than others in RRMM.
METHODS
We searched Cochrane Library, PubMed, Embase, and Web of Science for randomized controlled clinical trials receiving novel-drugs combined treatments as means of interventions. The primary endpoint was objective response rates (ORRs). We used the surface under the cumulative ranking curve (SUCRA) to sequence treatments. Totally, 22 randomized controlled trials were identified for final evaluation. With the aim to include all regimens within one network analysis, we divided the treatment schemes into 13 categories according to the use of novel drugs.
RESULTS
Carfilzomib-, daratumumab-, and isatuximab-based treatments had better ORRs than bortezomib combined dexamethasone and lenalidomide combined dexamethasone. Daratumumab- and isatuximab-based treatments had better ORRs than pomalidomide combined dexamethasone. According to the SUCRA, daratumumab- and isatuximab-based triple-drug regimens had higher probabilities of achieving better ORRs, followed by carfilzomib, elotuzumab, venetoclax, selinexor, ixazomib, vorinostat, pomalidomide, panobinostat, lenalidomide.
CONCLUSIONS
Our network meta-analysis performed a complete review of the ORRs of all current available novel-drugs based regimens for RRMM. By using the clinical data all from randomized controlled studies, daratumumab- and isatuximab-based treatments were identified to be the best treatments receiving better response quality.
Topics: Humans; Multiple Myeloma; Lenalidomide; Network Meta-Analysis; Bortezomib; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37343159
DOI: 10.1080/16078454.2023.2225342 -
BMC Medicine Sep 2023Colorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of...
BACKGROUND
Colorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening.
METHODS
We have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening.
RESULTS
We established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance.
CONCLUSIONS
This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.
Topics: Humans; Biological Specimen Banks; Drug Evaluation, Preclinical; Organoids; Adenoma; Colorectal Neoplasms; Metformin
PubMed: 37667332
DOI: 10.1186/s12916-023-03034-y -
BMC Pharmacology & Toxicology Sep 2023The study aims to investigate the apoptotic effects of combining LBH589 and AM1241 (a selective CB2 receptor agonist) on cervical cancer cells and elucidating the...
PURPOSE
The study aims to investigate the apoptotic effects of combining LBH589 and AM1241 (a selective CB2 receptor agonist) on cervical cancer cells and elucidating the mechanism of this combined therapy, which may provide innovative strategies for treating this disease.
METHODS
The viability of the cervical cancer cells was measured by cell counting kit-8 (CCK-8) assay, and the synergistic effect was analyzed using SynergyFinder. Cell proliferation was tested by cell cloning. The apoptosis and reactive oxygen species (ROS) production in cervical cancer cells were analyzed by flow cytometry. Western blot and quantitative real-time PCR (qRT-PCR) were employed to determine changes in protein and gene levels of pathway-related factors.
RESULTS
By the results of cytotoxicity assay, SiHa cells were selected and treated with 0.1 μM LBH589 and 4 μM AM1241 for 24 h for subsequent experiments. The combination of both was synergistic as determined by bliss, ZIP, HSA and LOEWE synergy score. Plate cloning results showed that LBH589 combined with AM1241 inhibited the proliferation of cervical cancer cells compared to individual drug. Additionally, compared with LBH589 alone, the combination of LBH589 and AM1241 induced autophagy by increasing LC3II/LC3I and decreasing P62/GAPDH, leading to a significantly higher rate of apoptosis. Pharmacological inhibition of also inhibited apoptosis. Consistently, we found that the endoplasmic reticulum, DNA damage repair pathway were induced after co-administration. Furthermore, cellular ROS increased after co-administration, and apoptosis was inhibited by the addition of ROS scavenger.
CONCLUSION
LBH589 combined with AM1241 activated the endoplasmic reticulum emergency pathway, DNA damage repair signaling pathway, oxidative stress and autophagy pathway, ultimately promoting the apoptosis of cervical cancer cells. These findings suggest that the co-administration of LBH589 and AM1241 may be a new treatment plan for the treatment of cervical cancer.
Topics: Female; Humans; Uterine Cervical Neoplasms; Panobinostat; Reactive Oxygen Species; Apoptosis; Autophagy
PubMed: 37740231
DOI: 10.1186/s40360-023-00686-7 -
Cancer Medicine Dec 2023Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for... (Review)
Review
BACKGROUND
Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for non-resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long-lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti-tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood-brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti-cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical agents with the BBB remain limited and do not provide a comprehensive explanation for the ineffectiveness of established anti-cancer drugs in PBT.
METHODS
We conducted our search for chemotherapeutic agents associated with the blood-brain barrier (BBB) using the following keywords: Chemotherapy in Cancer, Chemotherapy in Brain Cancer, Chemotherapy in PBT, BBB Inhibition of Drugs into CNS, Suboptimal Concentration of CNS Drugs, PBT Drugs and BBB, and Potential PBT Drugs. We reviewed each relevant article before compiling the information in our manuscript. For the generation of figures, we utilized BioRender software.
FOCUS
We focused our article search on chemical agents for PBT and subsequently investigated the role of the BBB in this context. Our search criteria included clinical trials, both randomized and non-randomized studies, preclinical research, review articles, and research papers.
FINDING
Our research suggests that, despite the availability of potent chemotherapeutic agents for several types of cancer, the effectiveness of these chemical agents in treating PBT has not been comprehensively explored. Additionally, there is a scarcity of studies examining the role of the BBB in the suboptimal outcomes of PBT treatment, despite the effectiveness of these drugs for other types of tumors.
Topics: Child; Humans; Blood-Brain Barrier; Quality of Life; Brain Neoplasms; Antineoplastic Agents
PubMed: 37997517
DOI: 10.1002/cam4.6647 -
Nature Communications Dec 2023The development of latency reversing agents that potently reactivate HIV without inducing global T cell activation would benefit the field of HIV reservoir research and...
The development of latency reversing agents that potently reactivate HIV without inducing global T cell activation would benefit the field of HIV reservoir research and could pave the way to a functional cure. Here, we explore the reactivation capacity of a lipid nanoparticle containing Tat mRNA (Tat-LNP) in CD4 T cells from people living with HIV undergoing antiretroviral therapy (ART). When combined with panobinostat, Tat-LNP induces latency reversal in a significantly higher proportion of latently infected cells compared to PMA/ionomycin (≈ 4-fold higher). We demonstrate that Tat-LNP does not alter the transcriptome of CD4 T cells, enabling the characterization of latently infected cells in their near-native state. Upon latency reversal, we identify transcriptomic differences between infected cells carrying an inducible provirus and non-infected cells (e.g. LINC02964, GZMA, CCL5). We confirm the transcriptomic differences at the protein level and provide evidence that the long non-coding RNA LINC02964 plays a role in active HIV infection. Furthermore, p24+ cells exhibit heightened PI3K/Akt signaling, along with downregulation of protein translation, suggesting that HIV-infected cells display distinct signatures facilitating their long-term persistence. Tat-LNP represents a valuable research tool for in vitro reservoir studies as it greatly facilitates the in-depth characterization of HIV reservoir cells' transcriptome and proteome profiles.
Topics: Virus Latency; Gene Products, tat; RNA, Viral; Nanoparticles; HIV Infections; Panobinostat; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; CD4 Antigens; HIV-1; Proviruses; Single-Cell Gene Expression Analysis; HIV Core Protein p24; RNA, Long Noncoding; Cells, Cultured; Humans; Ionomycin
PubMed: 38110433
DOI: 10.1038/s41467-023-44020-5 -
CNS Neuroscience & Therapeutics Feb 2024PSMD family members, as important components of the 26S proteasome, are well known to be involved in protein degradation. However, their role in glioblastoma (GBM) has...
AIMS
PSMD family members, as important components of the 26S proteasome, are well known to be involved in protein degradation. However, their role in glioblastoma (GBM) has not been rigorously investigated. We aimed to perform systematic analysis of the expression signature, prognostic significance and functions of PSMD family genes in GBM to reveal potential prognostic markers and new therapeutic targets among PSMD family members.
METHODS
In this study, we systemically analyzed PSMD family members in terms of their expression profiles, prognostic implications, DNA methylation levels, and genetic alterations; the relationships between their expression levels and immune infiltration and drug sensitivity; and their potential functional enrichment in GBM through bioinformatics assessment. Moreover, in vitro and in vivo experiments were used to validate the biological functions of PSMD9 and its targeted therapeutic effect in GBM.
RESULTS
The mRNA levels of PSMD5/8/9/10/11/13/14 were higher in GBM than in normal brain tissues, and the mRNA levels of PSMD1/4/5/8/9/11/12 were higher in high-grade glioma (WHO grade III & IV) than in low-grade glioma (WHO grade II). High mRNA expression of PSMD2/6/8/9/12/13/14 and low mRNA expression of PSMD7 were associated with poor overall survival (OS). Multivariate Cox regression analysis identified PSMD2/5/6/8/9/10/11/12 as independent prognostic factors for OS prediction. In addition, the protein-protein interaction network and gene set enrichment analysis results suggested that PSMD family members and their interacting molecules were involved in the regulation of the cell cycle, cell invasion and migration, and other biological processes in GBM. In addition, knockdown of PSMD9 inhibited cell proliferation, invasion and migration and induced G2/M cell cycle arrest in LN229 and A172 GBM cells. Moreover, PSMD9 promoted the malignant progression of GBM in vivo. GBM cell lines with high PSMD9 expression were more resistant to panobinostat, a potent deacetylase inhibitor, than those with low PSMD9 expression. In vitro and in vivo experiments further validated that PSMD9 overexpression rescued the GBM inhibitory effect of panobinostat.
CONCLUSION
This study provides new insights into the value of the PSMD family in human GBM diagnosis and prognosis evaluation, and we further identified PSMD9 as a potential therapeutic target. These findings may lead to the development of effective therapeutic strategies for GBM.
Topics: Humans; Glioblastoma; Panobinostat; Brain Neoplasms; Cell Line, Tumor; Glioma; Prognosis; Transcription Factors; RNA, Messenger; Gene Expression Regulation, Neoplastic; Proteasome Endopeptidase Complex
PubMed: 37485655
DOI: 10.1111/cns.14366 -
Cellular and Molecular Neurobiology Nov 2023Diabetic encephalopathy (DE) is one of the complications of diabetes mellitus with mild-to-moderate cognitive impairment. Trichostatin A (TSA) has been revealed to show...
Diabetic encephalopathy (DE) is one of the complications of diabetes mellitus with mild-to-moderate cognitive impairment. Trichostatin A (TSA) has been revealed to show protective effect on central nervous systems in Alzheimer's disease (AD) and hypoxic-ischemic brain injury. However, the effect and molecular mechanism of TSA on cognitive function of DE are unknown. Here, we demonstrated that cognitive function was damaged in diabetic mice versus normal mice and treatment with TSA improved cognitive function in diabetic mice. Proteomic analysis of the hippocampus revealed 174 differentially expressed proteins in diabetic mice compared with normal mice. TSA treatment reversed the expression levels of 111 differentially expressed proteins grouped into functional clusters, including the longevity regulating pathway, the insulin signaling pathway, peroxisomes, protein processing in the endoplasmic reticulum, and ribosomes. Furthermore, protein-protein interaction network analysis of TSA-reversed proteins revealed that UBA52, CAT, RPL29, RPL35A, CANX, RPL37, and PRKAA2 were the main hub proteins. Multiple KEGG pathway-enriched CAT and PRKAA2 levels were significantly decreased in the hippocampus of diabetic mice versus normal mice, which was reversed by TSA administration. Finally, screening for potential similar or ancillary drugs for TSA treatment indicated that HDAC inhibitors ISOX, apicidin, and panobinostat were the most promising similar drugs, and the PI3K inhibitor GSK-1059615, the Aurora kinase inhibitor alisertib, and the nucleophosmin inhibitor avrainvillamide-analog-6 were the most promising ancillary drugs. In conclusion, our study revealed that CAT and PRKAA2 were the key proteins involved in the improvement of DE after TSA treatment. ISOX, apicidin, and panobinostat were promising similar drugs and that GSK-1059615, alisertib, and avrainvillamide-analog-6 were promising ancillary drugs to TSA in the treatment of DE.
Topics: Mice; Animals; Panobinostat; Diabetes Mellitus, Experimental; Phosphatidylinositol 3-Kinases; Proteomics; Hippocampus; Diabetes Mellitus, Type 2
PubMed: 37864628
DOI: 10.1007/s10571-023-01424-7