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Cancers Oct 2021Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have... (Review)
Review
Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents.
PubMed: 34680358
DOI: 10.3390/cancers13205210 -
Experimental Hematology Jan 2020Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on...
Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on their synergism with the histone deacetylase inhibitor panobinostat (Pano) and the BCL2 inhibitor venetoclax/ABT199 was performed. Multiple myeloma cell lines MM.1R and MC/CAR were exposed to ∼IC levels of the drugs. Synergistic cytotoxicity was observed in cells exposed to the five-drug combination as indicated by combination indexes <1, supported by ∼86% inhibition of proliferation and ∼84% annexin V positivity in MM.1R and ∼58% inhibition of proliferation and ∼46% annexin V positivity in MC/CAR cells. Activation of the DNA damage response and apoptosis were suggested by a modest increase in the phosphorylation of ATM and its substrates; significant cleavage of PARP1, caspase 3, and heat shock protein 90; DNA fragmentation; mitochondrial membrane depolarization; and reactive oxygen species production. The five-drug combination significantly decreased the levels of PI3K, AKT, mTOR, RAPTOR, P-P70S6K, and eIF2α, with concomitant increases in P-AMPK and its substrate Tuberin/TSC2, suggesting that the mTOR signaling pathway was compromised. Endoplasmic reticulum stress through activation of the unfolded protein response was also observed as suggested by increases in the levels of calnexin, BiP/GRP78, ERO1-Lα, and protein disulfide isomerase, which may relate to venetoclax-mediated inhibition of BCL2 in the endoplasmic reticulum. This is the first report on the effects of a venetoclax-containing regimen on the unfolded protein response. These results provide a rationale to propose a clinical trial on use of Gem + Bu + Mel + Pano + Venetoclax as part of a conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Busulfan; Cell Line, Tumor; Cytotoxins; DNA Fragmentation; Deoxycytidine; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Melphalan; Membrane Potential, Mitochondrial; Multiple Myeloma; Neoplasm Proteins; Panobinostat; Signal Transduction; Sulfonamides; Gemcitabine
PubMed: 31954171
DOI: 10.1016/j.exphem.2020.01.003 -
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 -
Blood Advances Sep 2020Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the...
Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post-allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.
Topics: Adolescent; Adult; Aged; Decitabine; Hematopoietic Stem Cell Transplantation; Humans; Lymphocytes; Middle Aged; Panobinostat; Transplantation, Homologous; Young Adult
PubMed: 32936907
DOI: 10.1182/bloodadvances.2020002074 -
Pharmacotherapy Dec 2015Multiple myeloma is a neoplastic plasma cell disorder that is characterized by clonal proliferation of plasma cells in the bone marrow, monoclonal protein in the blood... (Review)
Review
Multiple myeloma is a neoplastic plasma cell disorder that is characterized by clonal proliferation of plasma cells in the bone marrow, monoclonal protein in the blood and/or urine, and associated organ dysfunction and biomarkers. There have been multiple recent advances in the relapsed and refractory setting. Major steps forward include the introduction of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide) in various combinations. These drugs have changed the management of multiple myeloma and have extended overall survival in the past decade. Established curative therapy is not yet available for patients diagnosed with multiple myeloma, supporting the development of new treatment targets. Histone deacetylase inhibitors have multiple proposed mechanisms of action in the treatment of multiple myeloma. Both vorinostat and panobinostat have demonstrated some activity against multiple myeloma, and due to the benefits reported with panobinostat, the U.S. Food and Drug Administration has recently approved the drug for the treatment of relapsed and refractory multiple myeloma. In this article, we describe the pharmacology, efficacy, and toxicity profile of vorinostat and panobinostat and their possible place in therapy.
Topics: Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Vorinostat
PubMed: 26684557
DOI: 10.1002/phar.1671 -
Therapeutic Advances in Hematology Dec 2014Panobinostat is an investigational and potent histone deacetylase inhibitor (HDACi) that has shown promise as an antimultiple myeloma agent in the preclinical setting.... (Review)
Review
Panobinostat is an investigational and potent histone deacetylase inhibitor (HDACi) that has shown promise as an antimultiple myeloma agent in the preclinical setting. In this review, we discuss the rationale for the use of panobinostat as a combination therapy for multiple myeloma and provide an overview of recent and ongoing clinical trials testing the safety and efficacy of panobinostat for the treatment of the disease.
PubMed: 25469210
DOI: 10.1177/2040620714552614 -
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 -
The Journal of Pharmacology and... Feb 2024Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its...
Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its efficacy for the treatment of tumors in the CNS following systemic administration when examined in different models or species. We conducted experiments using three different mouse strains or genotypes to have a more comprehensive understanding of the systemic as well as the CNS distributional kinetics of panobinostat. Our study found that panobinostat experienced rapid degradation in FVB mouse matrices and a faster degradation rate was observed at 37{degree sign}C compared with room temperature and 4{degree sign}C, suggesting that the instability of panobinostat was due to enzymatic metabolism. Panobinostat also showed inter-strain and inter-species differences in the plasma stability; and was stable in human plasma. The objective of this study was to examine the metabolic stability of panobinostat in different matrices and assess the influence of that metabolic stability on the pharmacokinetics and CNS delivery of panobinostat. Importantly, the plasma stability in various mouse strains was not reflected in the systemic pharmacokinetic behavior of panobinostat. Several hypotheses arise from this finding, including: the binding of panobinostat to red blood cells, the existence of competing endogenous compounds to enzyme(s), the distribution into tissues with a lower level of enzymatic activity or the metabolism occurring in the plasma is a small fraction of the total metabolism Panobinostat showed different degradation in plasma from different mouse strains and genotypes. However, despite the differences surrounding plasma stability, panobinostat showed similar pharmacokinetic behavior in different mouse models. This suggests that the inter-strain difference in enzymatic activity did not affect the pharmacokinetic behavior of panobinostat and its CNS distribution in mice. This lack of translation between metabolism assays and disposition can confound drug development.
PubMed: 38409112
DOI: 10.1124/jpet.123.002051 -
Dalton Transactions (Cambridge, England... May 2020We report the synthesis of two novel platinum(ii) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt(R,R-DACH)(Sub)] (1),...
We report the synthesis of two novel platinum(ii) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt(R,R-DACH)(Sub)] (1), [Pt(R,R-DACH)(panobinostat)] (2), where SubH = suberoyl-bis-hydroxamic acid; DACH = (1R,2R)-(-)-1,2-diaminocyclohexane and panobinostat = (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide. Complexes 1 and 2 were characterised by H, C, Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC values of 0.333 μM in SU-DIPG-IV, and 0.135 μM in SU-DIPG-XXI), complex 2 showed even greater cytotoxicities, with IC values of 0.021 μM (SU-DIPG-IV), 0.067 μM (BIOMEDE 194) and 0.009 μM (SU-DIPG-XXI). Complex 2 also demonstrated superior aqueous solubility in comparison to panobinostat. Complex 2 released free intact panobinostat under HPLC conditions, as determined by ESI-MS. Incubation of solutions of oxaliplatin (HO) and panobinostat (DMF) resulted in instantaneous reactivity and precipitation of a panobinostat derivative which was not a platinum complex; the same reactivity was not observed between carboplatin and panobinostat.
Topics: Antineoplastic Agents; Brain Stem Neoplasms; Cell Line, Tumor; Diffuse Intrinsic Pontine Glioma; Humans; Organoplatinum Compounds; Oxaliplatin; Panobinostat
PubMed: 32297619
DOI: 10.1039/c9dt04862f -
Neoplasia (New York, N.Y.) Feb 2022Histone deacetylase inhibitors (HDACi) sensitize homologous recombination (HR)-proficient human ovarian cancer cells to PARP inhibitors (PARPi). To investigate...
Histone deacetylase inhibitors (HDACi) sensitize homologous recombination (HR)-proficient human ovarian cancer cells to PARP inhibitors (PARPi). To investigate mechanisms of anti-tumor effects of combined HDACi/PARPi treatment we performed transcriptome analysis in HR- proficient human ovarian cancer cells and tested drug effects in established immunocompetent mouse ovarian cancer models. Human SKOV-3 cells were treated with vehicle (Con), olaparib (Ola), panobinostat (Pano) or Pano+Ola and RNA-seq analysis performed. DESeq2 identified differentially expressed HR repair and immune transcripts. Luciferised syngeneic mouse ovarian cancer cells (ID8-luc) were treated with the HDACi panobinostat alone or combined with olaparib and effects on cell viability, apoptosis, DNA damage and HR efficiency determined. C57BL/6 mice with intraperitoneally injected ID8-luc cells were treated with panobinostat and/or olaparib followed by assessment of tumor burden, markers of cell proliferation, apoptosis and DNA damage, tumor-infiltrating T cells and macrophages, and other immune cell populations in ascites fluid. There was a significant reduction in expression of 20/37 HR pathway genes by Pano+Ola, with immune and inflammatory-related pathways also significantly enriched by the combination. In ID8 cells, Pano+Ola decreased cell viability, HR repair, and enhanced DNA damage. Pano+Ola also co-operatively reduced tumor burden and proliferation, increased tumor apoptosis and DNA damage, enhanced infiltration of CD8+ T cells into tumors, and decreased expression of M2-like macrophage markers. In conclusion, panobinostat in combination with olaparib targets ovarian tumors through both direct cytotoxic and indirect immune-modulating effects.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Immunomodulation; Mice; Ovarian Neoplasms; Panobinostat; Phthalazines; Piperazines; Recombinational DNA Repair; Xenograft Model Antitumor Assays
PubMed: 34933276
DOI: 10.1016/j.neo.2021.12.002