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Cell Death & Disease May 2018Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease...
Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2/Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Humans; Membrane Potential, Mitochondrial; Mice, Inbred NOD; Mice, SCID; Mitochondria; Mitophagy; Models, Biological; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Quinacrine; Reactive Oxygen Species; Vorinostat
PubMed: 29789603
DOI: 10.1038/s41419-018-0679-6 -
Neuro-oncology Jul 2022
Topics: Brain Neoplasms; Child; Child, Preschool; Feasibility Studies; Humans; Infant; Isotretinoin; Vorinostat
PubMed: 35287175
DOI: 10.1093/neuonc/noac065 -
Acta Haematologica 2020In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional...
BACKGROUND
In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT.
PATIENTS AND METHODS
We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles.
RESULTS
The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression.
CONCLUSIONS
BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.
Topics: Bortezomib; Disease-Free Survival; Drug Administration Schedule; Female; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Male; Multiple Myeloma; Survival Rate; Transplantation, Autologous; Treatment Outcome; Vorinostat
PubMed: 31434076
DOI: 10.1159/000501298 -
Biology of Blood and Marrow... Jan 2020Post-autologous stem cell transplantation (ASCT) maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma (MM). Effective and...
Post-autologous stem cell transplantation (ASCT) maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma (MM). Effective and tolerable drug combinations may further enhance the clinical response post-ASCT. Vorinostat, a histone deacetylase inhibitor, induces antiproliferative and proapoptotic effects in patients with MM. We hypothesized that combination maintenance therapy would further prolong the clinical response achieved from transplantation. We previously reported that the combination of lenalidomide and vorinostat as maintenance post-ASCT was tolerable in 16 patients with MM. We now present the long-term follow up of these patients. Progression-free survival (PFS) and overall survival (OS) outcomes were characterized using the Kaplan-Meier method. Five patients (31%) had high-risk disease, and the median number of lines of therapy before ASCT was 1 (range, 1 to 5). With a median follow-up of 89.8 months from ASCT, the median PFS was 64.3 months (range, 21.7 months to not reached [NR]), and OS was not reached (median, 53.0 months to NR). At the time of this report, 5 patients remained on the study. The combination of vorinostat and lenalidomide as maintenance post-ASCT is tolerable and induces a durable response. A phase III randomized study of lenalidomide versus a combination with vorinostat is warranted.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Maintenance Chemotherapy; Male; Middle Aged; Multiple Myeloma; Survival Rate; Vorinostat
PubMed: 31518644
DOI: 10.1016/j.bbmt.2019.09.005 -
Biotechnology Journal Mar 2023Recombinant adeno-associated virus (rAAV) has established itself as a highly efficacious gene delivery vector with a well characterised safety profile allowing broad...
Recombinant adeno-associated virus (rAAV) has established itself as a highly efficacious gene delivery vector with a well characterised safety profile allowing broad clinical application. Recent successes in rAAV-mediated gene therapy clinical trials will continue to drive demand for improved rAAV production processes to reduce costs. Here, we demonstrate that small molecule bioactive chemical additives can significantly increase recombinant AAV vector production by human embryonic kidney (HEK) cells up to three-fold. Nocodazole (an anti-mitotic agent) and M344 (a selective histone deacetylase inhibitor) were identified as positive regulators of rAAV8 genome titre in a microplate screening assay. Addition of nocodazole to triple-transfected HEK293 suspension cells producing rAAV arrested cells in G2/M phase, increased average cell volume and reduced viable cell density relative to untreated rAAV producing cells at harvest. Final crude genome vector titre from nocodazole treated cultures was >2-fold higher compared to non-treated cultures. Further investigation showed nocodazole addition to cultures to be time critical. Genome titre improvement was found to be scalable and serotype independent across two distinct rAAV serotypes, rAAV8 and rAAV9. Furthermore, a combination of M344 and nocodazole produced a positive additive effect on rAAV8 genome titre, resulting in a three-fold increase in genome titre compared to untreated cells.
Topics: Humans; Genetic Vectors; HEK293 Cells; Dependovirus; Nocodazole; Vorinostat
PubMed: 36495042
DOI: 10.1002/biot.202200450 -
PloS One 2021Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory...
Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory drugs, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic that induces ER stress and is a commonly used model of AKI. 4-phenylbutyrate (4-PBA) is a chemical chaperone and histone deacetylase (HDAC) inhibitor and has been shown to protect the kidney from ER stress, apoptosis, and structural damage in a tunicamycin model of AKI. The renal protection provided by 4-PBA is attributed to its ability to prevent misfolded protein aggregation and inhibit ER stress; however, the HDAC inhibitor effects of 4-PBA have not been examined in the TM-induced model of AKI. As such, the main objective of this study was to determine if histone hyperacetylation provides any protective effects against TM-mediated AKI. The FDA-approved HDAC inhibitor vorinostat was used, as it has no ER stress inhibitory effects and therefore the histone hyperacetylation properties alone could be investigated. In vitro work demonstrated that vorinostat inhibited histone deacetylation in cultured proximal tubular cells but did not prevent ER stress or protein aggregation induced by TM. Vorinostat induced a significant increase in cell death, and exacerbated TM-mediated total cell death and apoptotic cell death. Wild type male mice were treated with TM (0.5 mg/kg, intraperitoneal injection), with or without vorinostat (50 mg/kg/day) or 4-PBA (1 g/kg/day). Mice treated with 4-PBA or vorinostat exhibited similar levels of histone hyperacetylation. Expression of the pro-apoptotic protein CHOP was induced with TM, and not inhibited by vorinostat. Further, vorinostat did not prevent any renal damage or decline in renal function caused by tunicamycin. These data suggest that the protective mechanisms found by 4-PBA are primarily due to its molecular chaperone properties, and the HDAC inhibitors used did not provide any protection against renal injury caused by ER stress.
Topics: Acute Kidney Injury; Animals; Cell Line; Disease Models, Animal; Endoplasmic Reticulum Stress; Histone Deacetylase Inhibitors; Male; Mice; Protein Aggregation, Pathological; Tunicamycin; Vorinostat
PubMed: 34847196
DOI: 10.1371/journal.pone.0260519 -
Medical Oncology (Northwood, London,... Oct 2022The process of cancer initiation and development is regulated via the transcriptional expression of cells going under genomic and epigenetic changes. Targeting...
The process of cancer initiation and development is regulated via the transcriptional expression of cells going under genomic and epigenetic changes. Targeting epigenetic "readers", i.e., bromodomains (BRD) and post-translational modifications of nucleosomal histone proteins regulate gene expression in both cancerous and healthy cells. In this study, the new epigenetic agent BRD inhibitor PLX51107 and histone deacetylase (HDAC) inhibitor SAHA' s (Vorinostat) single/combined applications' reflections were analyzed in case of cell proliferation, cytotoxicity, apoptosis, cell cycle arrest, and finally target gene expression regulation upon both AML and healthy B-lymphocyte cells; HL60 and NCIBL2171, respectively; in vitro. Since mono treatments of either Vorinostat or Plx51107 regulated cellular responses such as growth, proliferation, apoptosis, and cell cycle arrest of tumor cells; their combination treatments exerted accelerated results. We detected that combined treatment of Plx51107 and Vorinostat strengthened effects detected upon leukemic cells for gaining more sensitization to the agents, decreasing cell proliferation, dramatically inducing apoptosis, and cell cycle arrest; thus regulating target gene expressions. We have shown for the first time that the newly analyzed BRD inhibitor Plx51107 could be a promising therapeutic approach for hematological malignancies and its mono or combined usage might support a rapid transition to clinical trials.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Leukemia, Myeloid, Acute; Oxazoles; Pyridines; Pyrroles; Vorinostat
PubMed: 36224430
DOI: 10.1007/s12032-022-01858-x -
Blood Oct 2023
Topics: Humans; Hodgkin Disease; Programmed Cell Death 1 Receptor; Vorinostat; Lymphoma, Non-Hodgkin
PubMed: 37856096
DOI: 10.1182/blood.2023021283 -
Biochemistry. Biokhimiia Jul 2023Epigenetic genome regulation during malignant cell transformation is characterized by the aberrant methylation and acetylation of histones. Vorinostat (SAHA) is an...
Epigenetic genome regulation during malignant cell transformation is characterized by the aberrant methylation and acetylation of histones. Vorinostat (SAHA) is an epigenetic modulator actively used in clinical oncology. The antitumor activity of vorinostat is commonly believed to be associated with the inhibition of histone deacetylases, while the impact of this drug on histone methylation has been poorly studied. Using HeLa TI cells as a test system allowing evaluation of the effect of epigenetically active compounds from the expression of the GFP reporter gene and gene knockdown by small interfering RNAs, we showed that vorinostat not only suppressed HDAC1, but also reduced the activity of EZH2, SUV39H1, SUV39H2, and SUV420H1. The ability of vorinostat to suppress expression of EZH2, SUV39H1/2, SUV420H1 was confirmed by Western blotting. Vorinostat also downregulated expression of SUV420H2 and DOT1L enzymes. The data obtained expand our understanding of the epigenetic effects of vorinostat and demonstrate the need for a large-scale analysis of its activity toward other enzymes involved in the epigenetic genome regulation. Elucidation of the mechanism underlying the epigenetic action of vorinostat will contribute to its more proper use in the treatment of tumors with an aberrant epigenetic profile.
Topics: Vorinostat; Histone Methyltransferases; Genes, Reporter; Blotting, Western; Epigenesis, Genetic
PubMed: 37751867
DOI: 10.1134/S000629792307009X -
Oncology Reports Jan 2019Although different mechanisms of acquired resistance to epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors (TKIs) have been reported in non‑small...
Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation.
Although different mechanisms of acquired resistance to epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors (TKIs) have been reported in non‑small cell lung cancers (NSCLCs), the optimal treatment for patients with acquired resistance has not been clearly defined. The purpose of this study was to investigate the antitumor effects of gefitinib in combination with vorinostat, a potent histone deacetylase inhibitor (HDACI), and their associated molecular mechanisms in relation to activating apoptosis in NSCLC. The treatment using a combination of vorinostat and gefitinib was more potent in promoting cell death by activating apoptosis than gefitinib alone in parental PC9 cells that harbor an EGFR‑activating mutation (EGFR exon 19 deletion) and gefitinib‑resistant PC9 cells (PC9GR) with an EGFR T790M mutation. This combination induced heat shock protein 90 (HSP90) cleavage and reduced the level of HSP90 client proteins, including EGFR, MET and AKT, in PC9 and PC9GR cells. The addition of 4‑(2‑aminoethyl) benzenesulfonyl fluoride hydrochloride, a scavenger of reactive oxygen species (ROS), inhibited the degradation of HSP90 client proteins and HSP90 cleavage that was induced by co‑treatment as well as the cleavage of caspase‑3, caspase‑8, and caspase‑9 and cell death. We also observed that cleavage of HSP90 and its clients were blocked when caspases were inhibited. These results revealed that co‑treatment with vorinostat and gefitinib induced ROS‑dependent caspase activation, leading to the downregulation of HSP90 clients through HSP90 cleavage. Collectively, our findings provide a new basis for strategies that combine vorinostat with an EGFR‑TKI to reverse EGFR‑TKI resistance in NSCLC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Death; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; ErbB Receptors; Gefitinib; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Reactive Oxygen Species; Vorinostat
PubMed: 30365122
DOI: 10.3892/or.2018.6814