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Journal of Pharmaceutical Analysis Oct 2023Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of...
Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.
PubMed: 38024857
DOI: 10.1016/j.jpha.2023.06.005 -
Pharmaceutical Biology Sep 2016Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown... (Review)
Review
Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown encouraging results in haematological malignancies, but the poor pharmacokinetic of these inhibitors leads to insufficient tumour concentration limiting their application against solid malignancies. Objective This article deals with novel HDAC inhibitor pracinostat (SB939) and delineates its therapeutic role in solid and haematological malignancies. The article provides rigorous details about the underlying molecular mechanisms modulated by pracinostat to exert cytotoxic effect. The article further highlights the doublet therapy that may be used to tackle monotonous cancer chemoresistance. Methods Both old and the latest literature on pracinostat was retrieved from diverse sources, such as PubMed, Science Direct, Springer Link, general Google search using both pracinostat and SB939 keywords in various ways: after thorough evaluation the topic which can fulfil the current gap was chosen. Results Pracinostat shows potent anticancer activity against both solid and haematological malignancies compared to the FDA-approved drug vorinostat. This marvellous inhibitor has better physicochemical, pharmaceutical and pharmacokinetic properties than the defined inhibitor vorinostat. Pracinostat has >100-fold more affinity towards HDACs compared to other zinc-dependent metalloenzymes and shows maximum efficacy when used in doublet therapy. Conclusion Pracinostat shows potent anticancer activity even against therapeutically challenging cancers when used in doublet therapy. However, the triplet combination studies of the defined inhibitor that may prove even more beneficial are still undone, emphasizing the desperate need of further research in the defined gap.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Neoplasms; Treatment Outcome
PubMed: 26853619
DOI: 10.3109/13880209.2015.1135966 -
Pharmacological Research Jan 2021HDAC6, a class IIB HDAC isoenzyme, stands unique in its structural and physiological functions. Besides histone modification, largely due to its cytoplasmic... (Review)
Review
HDAC6, a class IIB HDAC isoenzyme, stands unique in its structural and physiological functions. Besides histone modification, largely due to its cytoplasmic localization, HDAC6 also targets several non-histone proteins including Hsp90, α-tubulin, cortactin, HSF1, etc. Thus, it is one of the key regulators of different physiological and pathological disease conditions. HDAC6 is involved in different signaling pathways associated with several neurological disorders, various cancers at early and advanced stage, rare diseases and immunological conditions. Therefore, targeting HDAC6 has been found to be effective for various therapeutic purposes in recent years. Though several HDAC6 inhibitors (HDAC6is) have been developed till date, only two ACY-1215 (ricolinostat) and ACY-241 (citarinostat) are in the clinical trials. A lot of work is still needed to pinpoint strictly selective as well as potent HDAC6i. Considering the recent crystal structure of HDAC6, novel HDAC6is of significant therapeutic value can be designed. Notably, the canonical pharmacophore features of HDAC6is consist of a zinc binding group (ZBG), a linker function and a cap group. Significant modifications of cap function may lead to achieve better selectivity of the inhibitors. This review details the study about the structural biology of HDAC6, the physiological and pathological role of HDAC6 in several disease states and the detailed structure-activity relationships (SARs) of the known HDAC6is. This detailed review will provide key insights to design novel and highly effective HDAC6i in the future.
Topics: Animals; Drug Discovery; Histone Deacetylase 6; Humans; Neoplasms; Neurodegenerative Diseases
PubMed: 33171304
DOI: 10.1016/j.phrs.2020.105274 -
Molecular Biology Reports Aug 2022Glioma is the most common malignant brain tumor in adults. The effects of conventional treatment regimens are still limited to prolonging the survival of patients....
INTRODUCTION
Glioma is the most common malignant brain tumor in adults. The effects of conventional treatment regimens are still limited to prolonging the survival of patients. Histone deacetylases (HDACs) are potential targets for tumor treatment. Pracinostat is a new type of HDAC inhibitor (HDACi) that has a significant antitumor effect on a variety of tumors. Thus, we aim to investigate the role of pracinostat in human glioma and explored its underlying mechanism.
METHODS
Cell viability, proliferation and apoptosis of human glioma cell lines were measured by Cell Counting kit 8 and flow cytometry. Pathway verification and protein interaction were determined by quantitative real-time polymerase chain reaction, Western blotting and immunofluorescence staining. Transwell technology was used to assess the migration and invasion of cells. Clinical significance of TIMP3, MMP9 and MMP2 in glioma was analyzed through The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database.
RESULTS
Functionally, pracinostat not only inhibited proliferation and induced apoptosis but also inhibited migration and invasion in human glioma cell lines. Mechanistically, pracinostat increased the expression of TIMP3 and decreased the expression of MMP2, MMP9 and VEGF in human glioma cells in vitro and in vivo. In addition, pracinostat inhibited both the PI3K/Akt signaling pathway and the STAT3 pathway.
CONCLUSIONS
Our results strongly support the potential clinical use of pracinostat as a novel therapy for human glioma in the near future.
Topics: Adult; Apoptosis; Benzimidazoles; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glioma; Histone Deacetylase Inhibitors; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Phenotype; Phosphatidylinositol 3-Kinases
PubMed: 35622308
DOI: 10.1007/s11033-022-07559-y -
Blood Advances Feb 2019Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity...
Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Benzimidazoles; Female; Humans; Leukemia, Myeloid, Acute; Male; Survival Analysis; Treatment Outcome
PubMed: 30760466
DOI: 10.1182/bloodadvances.2018027409 -
Leukemia & Lymphoma Jul 2019Although ruxolitinib improves symptoms and splenomegaly in patients with advanced myelofibrosis, whether this agent is truly disease-modifying remains unclear. Histone...
Although ruxolitinib improves symptoms and splenomegaly in patients with advanced myelofibrosis, whether this agent is truly disease-modifying remains unclear. Histone deacetylase inhibitors (HDACi) downregulate JAK2 via interference with chaperone function. Pracinostat, a pan-HDACi, has modest single-agent activity in myelofibrosis. We conducted a single-institution, phase 2, investigator-initiated trial of ruxolitinib plus pracinostat (begun after 12 weeks of ruxolitinib) in 25 patients with myelofibrosis, of whom 20 received both agents. Sixteen (80%) patients had objective responses (all 'clinical improvement'). The rate of spleen response (by palpation) was 74%, and that of symptom response 80%. Most responses occurred prior to pracinostat initiation. Three patients experienced improvement in bone marrow fibrosis, and one a near-complete molecular response after two years on study treatment. All patients discontinued pracinostat and are currently off-study. Pracinostat interruptions and dose reductions were frequent, often due to worsening anemia. These findings do not support continued development of pracinostat in myelofibrosis.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Primary Myelofibrosis; Prognosis; Pyrazoles; Pyrimidines; Survival Rate
PubMed: 30632841
DOI: 10.1080/10428194.2018.1543876 -
Leukemia Research Dec 2022
Topics: Humans; Gemtuzumab; Benzimidazoles; Leukemia, Myeloid, Acute
PubMed: 36401944
DOI: 10.1016/j.leukres.2022.106984 -
Life Sciences May 2020Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic...
AIMS
Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms.
MAIN METHODS
MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects.
KEY FINDINGS
Our results demonstrated that SB939 at 0.5-1 μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models.
SIGNIFICANCE
Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.
Topics: Animals; Antigens, CD; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Interleukin-6; Lung Neoplasms; Mice; Mice, Nude; Repressor Proteins; STAT3 Transcription Factor; Signal Transduction; Tumor Burden; Vimentin; Xenograft Model Antitumor Assays
PubMed: 32109485
DOI: 10.1016/j.lfs.2020.117469 -
Leukemia Research May 2024Non-intensive therapies such as the hypomethylating agent (HMA) azacitidine (AZA) have been used in patients with AML ineligible for intensive induction chemotherapy... (Randomized Controlled Trial)
Randomized Controlled Trial
Non-intensive therapies such as the hypomethylating agent (HMA) azacitidine (AZA) have been used in patients with AML ineligible for intensive induction chemotherapy (IC) or stem cell transplant due to advanced age, comorbidities, and/or risk factors. However, response rates and survival remain dismal. Pre-clinical studies indicate the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes synergistically. The activity of pracinostat, an oral pan-HDAC inhibitor, has been shown in xenograft tumor models of AML and promising efficacy was seen in a Phase 2 study. This Phase 3 study (NCT03151408) evaluated the efficacy/safety of pracinostat administered with AZA in adult patients with newly diagnosed AML ineligible to receive IC. Patients were randomized to either pracinostat plus AZA or placebo/AZA and stratified by cytogenetic risk and ECOG status. As planned, an interim analysis was performed when 232/390 events (deaths) occurred. A total of 406 patients were randomized (203/group) at the time of the analysis. Median overall survival was 9.95 months for both treatment groups (p=0.8275). There was no significant difference between treatments in secondary efficacy endpoints, reflecting a lack of clinical response. This study did not show a benefit of adding pracinostat to AZA in elderly patients unfit for IC.
Topics: Humans; Leukemia, Myeloid, Acute; Male; Aged; Female; Middle Aged; Azacitidine; Antineoplastic Combined Chemotherapy Protocols; Adult; Aged, 80 and over; Induction Chemotherapy; Aminopyridines; Benzamides
PubMed: 38499457
DOI: 10.1016/j.leukres.2024.107480 -
Chemical Biology & Drug Design Aug 2019A series of compounds similar to Pracinostat that contained benzimidazole ring and N-hydroxyacrylamide attached at 5- or 6-position were designed, synthesized, and...
A series of compounds similar to Pracinostat that contained benzimidazole ring and N-hydroxyacrylamide attached at 5- or 6-position were designed, synthesized, and evaluated as HDAC inhibitors. It was interesting to find that the corresponding derivative 1 with N-hydroxyacrylamide attached at 5-position was a potent HDAC inhibitor while the others at 6-position were not. This is the first time to demonstrate the position difference plays important role in the HDAC inhibitory activities of the cinnamic hydroxamates.
Topics: Benzimidazoles; HeLa Cells; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans
PubMed: 30932330
DOI: 10.1111/cbdd.13527