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Pharmaceuticals (Basel, Switzerland) Jul 2021Among the well-established alterations contributing to prostate cancer (PCa) pathogenesis, epigenetics is an important player in its development and aggressive disease...
Among the well-established alterations contributing to prostate cancer (PCa) pathogenesis, epigenetics is an important player in its development and aggressive disease state. Moreover, since no curative therapies are available for advanced stage disease, there is an urgent need for novel therapeutic strategies targeting this subset of patients. Thus, we aimed to evaluate the combined antineoplastic effects of DNA methylation inhibitor hydralazine and histone deacetylase inhibitors panobinostat and valproic acid in several prostate cell lines. The effect of these drugs was assessed in four PCa (LNCaP, 22Rv1, DU145 and PC-3) cell lines, as well as in non-malignant epithelial (RWPE-1) and stromal (WPMY-1) cell lines, using several assays to evaluate cell viability, apoptosis, proliferation, DNA damage and clonogenic potential. We found that exposure to each epidrug separately reduced viability of all PCa cells in a dose-dependent manner and that combined treatments led to synergic growth inhibitory effects, impacting also on colony formation, invasion, apoptotic and proliferation rates. Interestingly, antitumoral effects of combined treatment were particularly expressive in DU145 cells. We concluded that hydralazine and panobinostat attenuate malignant properties of PCa cells, constituting a potential therapeutic tool to counteract PCa progression.
PubMed: 34358096
DOI: 10.3390/ph14070670 -
Oncology and Therapy 2016The histone deacetylase (HDAC) inhibitors have been demonstrated as an emerging class of anticancer drugs. HDACs are involved in regulation of gene expression and in... (Review)
Review
The histone deacetylase (HDAC) inhibitors have been demonstrated as an emerging class of anticancer drugs. HDACs are involved in regulation of gene expression and in chromatin remodeling, thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac, LBH589) was developed by Novartis Pharmaceuticals and has been recently approved by the US Food and Drug Administraion (FDA) as a drug to treat multiple myeloma. It is under clinical investigation for a range of haematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and non-histone proteins as well as various apoptotic, autophagy-mediated targets and various tumorogenesis pathways involved in development of tumors. The optimal combination regimen for pancreatic cancer remains to be fully elucidated with various combination regimens, and should be investigated in clinical trials. This article summarizes the current preclinical and clinical status of panobinostat in pancreatic cancer. Preclinical data suggests that panobinostat has potential inhibitory activity in pancreatic cancer cells by targeting various pathways and factors involved in the development of cancer. Herein, we reviewed the status of mono and combination therapy and the rationale behind the combination therapy undergoing trials, as well as possible future prospective use in the treatment of pancreatic cancer.
PubMed: 28261641
DOI: 10.1007/s40487-016-0023-1 -
Scientific Reports Aug 2023Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting...
Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.
Topics: Humans; Panobinostat; Histone Deacetylase Inhibitors; Glioma; Antineoplastic Agents; Chromatin; Isocitrate Dehydrogenase; Mutation; Brain Neoplasms; Histone Deacetylase 1; Histone Deacetylase 6
PubMed: 37528157
DOI: 10.1038/s41598-023-33889-3 -
Nature Biotechnology Dec 2022Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated...
Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated high-throughput and high-content techniques-an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses and multiplexed imaging of tumor microenvironmental states-to investigate the tumor cell and immunological response signatures to different treatment regimens. Using a mouse model of breast cancer, we identified effective combinations from among numerous agents within days. In vivo studies in three immunocompetent mammary carcinoma models demonstrated that the predicted combinations synergistically increased therapeutic efficacy. We identified at least five promising treatment strategies, of which the panobinostat, venetoclax and anti-CD40 triple therapy was the most effective in inducing complete tumor remission across models. Successful drug combinations increased spatial association of cancer stem cells with dendritic cells during immunogenic cell death, suggesting this as an important mechanism of action in long-term breast cancer control.
Topics: Humans; Immunotherapy; Panobinostat; Antineoplastic Agents; Drug Delivery Systems; Neoplasms; Cell Line, Tumor
PubMed: 35788566
DOI: 10.1038/s41587-022-01379-y -
British Journal of Clinical Pharmacology Feb 2023Multiple myeloma accounts for over 10-15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of... (Review)
Review
AIMS
Multiple myeloma accounts for over 10-15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of multiple myeloma. Four drugs were approved by the Food and Drug Administration (FDA) in 2015, but their safety is not well defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs.
METHODS
We reviewed the adverse cardiac events of newly approved FDA drugs since 2015 using the US FDA Adverse Events Reporting System (FAERS) database. We calculated the reporting odds ratio (ROR) with 95% confidence interval (CIs) for the drugs that have the highest incidence of cardiovascular adverse events.
RESULTS
Among the medications that have approved for multiple myeloma between 2015 and 2020, 4 novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, ixazomib, daratumumab and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6) and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7) and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3 (1.9-2.8) and 4.6 (3.2-6.6) due to elotuzumab, ixazomib, daratumumab and panobinostat compared to all other drugs in FAERS.
CONCLUSION
Our results demonstrated that certain newly approved antimyeloma therapies are significantly associated with previously unknown cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.
Topics: Humans; United States; Multiple Myeloma; Pharmacovigilance; Cardiotoxicity; Panobinostat; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration
PubMed: 35996166
DOI: 10.1111/bcp.15499 -
Scientific Reports May 2017Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the...
Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic with activity in both diseases. Dose-dependent synergy was observed in Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines and was due to senescence rather than potentiation of cell death. Senescence occurred following cisplatin- or Taxol-treatment in cell lines from both cancer types and was associated with decreased histone 3 (H3) acetylation and increased Bcl-xL expression: the latter a biomarker of senescence and target of anti-senescence therapeutics, or senolytics. Since H3 acetylation and Bcl-xL expression were altered in senescence, we subsequently evaluated pano as a senolytic in chemotherapy-treated cancer cells enriched for senescent cells. Pano caused cell death at significantly higher rates compared to repeat dosing with chemotherapy. This was associated with decreased expression of Bcl-xL and increased acetylated H3, reversing the expression patterns observed in senescence. These data support evaluating pano as a post-chemotherapy senolytic with the potential to kill persistent senescent cells that accumulate during standard chemotherapy in NSCLC and HNSCC.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Cellular Senescence; Dose-Response Relationship, Drug; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Lung Neoplasms; Paclitaxel; Panobinostat; Squamous Cell Carcinoma of Head and Neck
PubMed: 28507307
DOI: 10.1038/s41598-017-01964-1 -
Journal of Cancer Research and Clinical... Sep 2013Advanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo...
PURPOSE
Advanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo activity of two relatively new histone deacetylase inhibitors (HDACIs), belinostat and panobinostat, and a variety of tyrosine kinase inhibitors (TKIs) against a panel of nine human thyroid cancer cell lines.
METHODS
The anti-proliferative activity and the effects of HDACIs, TKIs and their combinations on thyroid cancer cells were determined by cytotoxicity assays, microarray and immunoblot analyses. Synergism between HDACIs and TKIs was assessed by the median effects model of Chou-Talalay (Calcusyn(®)).
RESULTS
Belinostat and panobinostat were active against the thyroid cancer cell lines irrespective of their mutational composition, and belinostat was effective in preventing growth of human thyroid cancer xenografts in immunodeficient mice. Further studies showed that both HDACIs induced apoptosis. HDACI also elevated acetylated histone 3, p21(Waf), and PARP, and decreased levels of phosphorylated ERK and AKT (Ser473). RNA assay analysis suggested both HDACIs modulated genes associated with the cell cycle, DNA damage and apoptosis. Most of the TKI (pazopanib, motesanib, sorafenib and dasatinib) were either inactive in vitro or were active only at high doses. However, the novel combinations of either pazopanib or dasatinib TKIs with either belinostat or panobinostat synergistically inhibited cell growth of thyroid cancer cells in vitro.
CONCLUSIONS
In summary, these HDACIs either alone or combined with selected TKIs may have a role in treatment of aggressive thyroid cancer.
Topics: Acetylation; Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; In Vitro Techniques; Indoles; Mice; Mice, Nude; Panobinostat; Sulfonamides; Thyroid Neoplasms; Xenograft Model Antitumor Assays
PubMed: 23824064
DOI: 10.1007/s00432-013-1465-6 -
Cancer Science Nov 2016Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities... (Review)
Review
Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.
Topics: Animals; Calcineurin; Hematologic Neoplasms; Histone Deacetylase Inhibitors; Humans; Leukemia, Myeloid, Acute; Lymphoma, T-Cell; Multiple Myeloma
PubMed: 27554046
DOI: 10.1111/cas.13062 -
British Journal of Haematology Oct 2017Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with... (Randomized Controlled Trial)
Randomized Controlled Trial
Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Dexamethasone; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Multiple Myeloma; Panobinostat; Recurrence; Transplantation, Autologous; Treatment Outcome
PubMed: 28653400
DOI: 10.1111/bjh.14821 -
Cancer Chemotherapy and Pharmacology Sep 2021Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with...
PURPOSE
Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with increased activity against H3K27M mutant cell lines. Given limited evidence regarding the CNS penetration of panobinostat, we sought to characterize its BBB penetration in a murine model.
METHODS
Panobinostat 15 mg/kg was administered IV to 12 CD-1 female mice. At specified time points, mice were euthanized, blood samples were collected, and brains were removed. LC-MS was performed to quantify panobinostat concentrations. C and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines.
RESULTS
Mean panobinostat plasma concentrations (ng/mL) were 27.3 ± 2.5 at 1 h, 7.56 ± 1.8 at 2 h, 1.48 ± 0.56 at 4 h, and 2.33 ± 1.18 at 7 h. Mean panobinostat brain concentrations (ng/g) were 60.5 ± 6.1 at 1 h, 42.9 ± 5.4 at 2 h, 33.2 ± 6.1 at 4 h, and 28.1 ± 4.3 at 7 h. Brain-to-plasma ratio at 1 h was 2.22 and the brain to plasma AUC ratio was 2.63. Based on the published human pharmacokinetic data, the anticipated C in humans is expected to be significantly higher than the IC-50 identified in DIPG models.
CONCLUSION
It is expected that panobinostat would be effective in CNS tumors where the IC-50 is in the low nanomolar range. Thus, our data demonstrate panobinostat crosses the BBB and achieves concentrations above the IC-50 for DIPG and other brain tumors and should be explored further for clinical efficacy.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Blood-Brain Barrier; Brain; Female; Histone Deacetylase Inhibitors; Inhibitory Concentration 50; Mice; Panobinostat; Tissue Distribution
PubMed: 34115161
DOI: 10.1007/s00280-021-04313-2