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Clinical Cancer Research : An Official... Apr 2001We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors...
PURPOSE
We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid) is a new member of this class of compounds that is currently under development as an anticancer agent. We investigated the activity of pyroxamide as an inducer of differentiation and/or apoptosis in transformed cells.
EXPERIMENTAL DESIGN AND RESULTS
Pyroxamide, at micromolar concentrations, induced terminal differentiation in murine erythroleukemia (MEL) cells and caused growth inhibition by cell cycle arrest and/or apoptosis in MEL, prostate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused little evident toxicity significantly suppressed the growth of s.c. CWR22 prostate cancer xenografts. Despite the potent growth-inhibitory effects of pyroxamide in this tumor model, serum prostate-specific antigen levels in control versus pyroxamide-treated mice were not significantly different. Pyroxamide is a potent inhibitor of affinity-purified HDAC1 (ID(50) = 100 nM) and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Human CWR22 prostate tumor xenografts from mice treated with pyroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetylation and increased expression of the cell cycle regulator p21/WAF1, compared with tumors from vehicle-treated control animals.
CONCLUSIONS
The findings suggest that pyroxamide may be a useful agent for the treatment of malignancy and that induction of p21/WAF1 in transformed cells by pyroxamide may contribute to the antitumor effects of this agent.
Topics: Acetylation; Aminopyridines; Animals; Antineoplastic Agents; Cell Differentiation; Cell Division; Cell Line, Transformed; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Disease Models, Animal; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 11309347
DOI: No ID Found -
Current Medicinal Chemistry.... Jul 2002Recent reports have shown that pharmacological manipulation of chromatin remodeling by histone deacetylase (HDAC) inhibitors, might develop into a potent and specific... (Review)
Review
Recent reports have shown that pharmacological manipulation of chromatin remodeling by histone deacetylase (HDAC) inhibitors, might develop into a potent and specific strategy for the treatment of cancer. Alterations in histone acetylation may lead to changes in chromatin structure and transcriptional dysregulation of genes that are implicated in controlling either cell cycle progression or pathways regulating cell differentiation and/or apoptosis. Dimethyl sulphoxide was one of the first chemicals to be identified as an inducer of transformed cell differentiation. In the class of HDAC inhibitors, now included a short-chain fatty acids, such as 4-phenylbutyrate and valporic acid, hydroxamic acids, such as suberoylanilide hydroxamic acid (SAHA), pyroxamide, trichostatin A, oxamflatin and CHAPSs, cyclic tetrapeptides, such as trapoxin, apicidin and depsipeptide-also known as FK-228 or FR 901228, and benzamides, such as MS-275. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. Thus, HDAC inhibitors remains one of the most promising class of new anticancer agents. Further studies are needed in order to delineate the optimal dosage, the duration of therapy and possibly the efficacy of other agents able to synergize with HDAC inhibitors in the fight against cancer.
Topics: Animals; Antineoplastic Agents; Cell Physiological Phenomena; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Neoplasms; Structure-Activity Relationship
PubMed: 12678732
DOI: 10.2174/1568011023353921 -
Oncogene Jan 2021Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified...
Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified FRMD6 (FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon FRMD6 knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for FRMD6 deficient PC cells. Finally, we established orthotropic Frmd6 and Pten, or Pten only (control) knockout in the ROSA26 mouse prostate. After 12 weeks, Frmd6/Pten double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while Pten single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion, FRMD6 was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC.
Topics: Aged; Aminopyridines; Animals; Cell Proliferation; Cytoskeletal Proteins; DNA Methylation; Down-Regulation; Hippo Signaling Pathway; Humans; Hydroxamic Acids; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Middle Aged; PTEN Phosphohydrolase; Prognosis; Promoter Regions, Genetic; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 33249427
DOI: 10.1038/s41388-020-01548-w -
Oncology Reports Feb 2006Accumulating evidence suggests that the acetylation and deacetylation of histones play significant roles in transcriptional regulation of eukaryotic cells. The balance... (Review)
Review
Accumulating evidence suggests that the acetylation and deacetylation of histones play significant roles in transcriptional regulation of eukaryotic cells. The balance between acetylation and deacetylation is an important factor in regulating gene expression and is thus linked to the control of cell fate. The histone deacetylase inhibitors (HDIs) including the hydroxamic acids, such as suberoylanilide hydroxamic acid and pyroxamide, the benzamides MS-275 and CI-994 and the butyrate derivative 4-PBA are a new class of anti-neoplastic agents currently being evaluated in clinical trials. Moreover, new synthetic HDIs have been used recently in phase I and II clinical trials. Over the next few years experts believe that as first generation HDIs produce clinical benefits and second generation inhibitors are rationally designed with improved specificity, this class of drugs will emerge as a new way of cancer treatment. The first clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. The use of HDIs, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients. Further evaluation is needed to establish the clinical activity of combination therapy using HDIs with cytotoxic drugs or differentiation induced agents.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Histone Deacetylases; Histones; Humans; Neoplasms
PubMed: 16391874
DOI: No ID Found -
Clinical Cancer Research : An Official... Nov 2003A group of histone deacetylase inhibitors has been shown to be effective in suppressing the growth of a variety of transformed cell lines in vitro and in vivo. The...
PURPOSE
A group of histone deacetylase inhibitors has been shown to be effective in suppressing the growth of a variety of transformed cell lines in vitro and in vivo. The effects of two of these agents, suberoylanilide hydroxamic acid (SAHA) and suberoyl-3-aminopyridineamide hydroxamic acid (pyroxamide), were investigated for their growth-suppressive effects on rhabdomyosarcoma (RMS) cells.
EXPERIMENTAL DESIGN AND RESULTS
Dose-response experiments of two RMS cell lines, RD (embryonal) and RH30B (alveolar), were performed with SAHA (0.25-3.0 micro M) and pyroxamide (1.25-20.0 micro M). Both agents caused a dose-dependent decrease in viable cell number and an increase in percentage of dead cells over time. Exposure of the RMS cells to SAHA and pyroxamide resulted in an accumulation of acetylated histones with increasing doses by Western blot analysis. Additionally, there was an induction of p21/WAF1 at 15 and 24 h when the cells were cultured with SAHA (2.0 micro M) or pyroxamide (20.0 micro M), concentrations that were tested because they successfully induced inhibition of cell growth and initiated cell death in both RMS cell lines. An increase in nuclei with hypodiploid or sub-G(1) fraction was found by flow cytometry with increasing doses of both SAHA (0.25-3.0 micro M) and pyroxamide (1.25-20.0 micro M) over time. This finding is consistent with DNA fragmentation and cell death by apoptosis.
CONCLUSIONS
SAHA and pyroxamide induce growth suppression and cell death in human RMS in vitro. Accumulation of acetylated histones and induction of p21/WAF1 expression are observed in cells exposed to either agent.
Topics: Acetylation; Cell Death; Cell Division; Cell Line, Tumor; Enzyme Inhibitors; Flow Cytometry; Histone Deacetylase Inhibitors; Histones; Humans; Kinetics; Rhabdomyosarcoma
PubMed: 14654560
DOI: No ID Found -
Current Treatment Options in Oncology Apr 2001The implementation of new drug treatments has improved the prognosis for advanced cancers of the cervix, uterus, and ovary. Platinum analogs are the most effective drugs... (Review)
Review
The implementation of new drug treatments has improved the prognosis for advanced cancers of the cervix, uterus, and ovary. Platinum analogs are the most effective drugs in the treatment of ovarian cancer. Other drugs, such as oxaliplatin, have been proposed as a rational treatment of platinum refractory ovarian cancer. Epothilones are also being studied in clinical trials, as are histone deacetylase inhibitors. Several promising agents may soon receive Food and Drug Administration approval.
Topics: Aminopyridines; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boronic Acids; Bortezomib; Cisplatin; Female; Gefitinib; Genital Neoplasms, Female; Humans; Hydroxamic Acids; Lactams, Macrocyclic; Organoplatinum Compounds; Paclitaxel; Protein-Tyrosine Kinases; Pyrazines; Quinazolines; Trastuzumab
PubMed: 12057130
DOI: 10.1007/s11864-001-0054-0 -
Biology Oct 2022Previous studies have shown that some of the histone deacetylases (HDACs) play diverse roles in the regulation of ovarian somatic cell development, oocyte maturation and...
Previous studies have shown that some of the histone deacetylases (HDACs) play diverse roles in the regulation of ovarian somatic cell development, oocyte maturation and early embryonic development in different species including sheep. This study aimed to clarify whether HDAC1 also played pivotal roles in regulating oocyte maturation in Tan sheep. The results showed that HDAC1 was expressed in the nuclei of both the granulosa cells and oocytes of the growing follicles in the Tan sheep's ovaries. However, the level of HDAC1 was unaffected by luteinizing hormone (LH) induction in cultured granulosa cells. Meanwhile, the specific inhibition of HDAC1 using pyroxamide did not induce significant changes in the expression levels of EGF-like growth factors in vitro, whereas both the cumulus expansion and oocyte maturation of the cultured cumulus oocyte complexes (COCs) were significantly inhibited by pyroxamide. Additionally, the numbers of histone acetylation sites (H4K5, H4K12, H3K14 and H3K9) in ovarian granulosa cells were significantly increased. In conclusion, a constant expression of HDAC1 in the growing follicles of Tan sheep may be pivotal for supporting oocyte growth and maturation, although its action may not be closely correlated with LH induction, nor does it directly affect the expression of the EGF-like factors. Our study implies that there may exist diverse functions of the respective HDACs in modulating female reproduction in sheep.
PubMed: 36290368
DOI: 10.3390/biology11101464 -
Biochemical and Biophysical Research... Oct 2023Although the prognosis for papillary thyroid carcinoma (PTC) is generally good, a certain proportion of patients show recurrent or advanced disease, indicating the need...
Although the prognosis for papillary thyroid carcinoma (PTC) is generally good, a certain proportion of patients show recurrent or advanced disease, indicating the need for further development of targeted medications. The purpose of this study was to explore the interventional effects of colchicine on PTC and the potential mechanisms or targets. We obtained PTC-related targets from the database and colchicine targets by predicting them. We screened the common targets of colchicine and the PTC-related target histone deacetylase 1 (HDAC1) and verified through molecular docking that colchicine has a good affinity for HDAC1, i.e., colchicine may act on PTC by affecting HDAC1. We then used CCK-8, colony formation, mitochondrial membrane potential and apoptosis assays to confirm that colchicine could inhibit the proliferation and promote the apoptosis of PTC cells and verified by RT‒qPCR, Western blot, and cellular immunofluorescence assays that colchicine could inhibit the expression of HDAC1 in PTC cells. The cytotoxicity and inhibitory effect of colchicine on HDAC1 in PTC cells was stronger than that in normal thyroid cells. We then applied an HDAC1 inhibitor, pyroxamide, to verify that inhibition of HDAC1 inhibits proliferation and promotes apoptosis in PTC cells. Therefore, we conclude that colchicine can inhibit the proliferation and promote the apoptosis of PTC cells likely due to its inhibitory effect on HDAC1. This finding implies that colchicine may be helpful for therapeutic intervention in PTC and that HDAC1 may be a promising clinical therapeutic target.
Topics: Humans; Thyroid Cancer, Papillary; MicroRNAs; Thyroid Neoplasms; Histone Deacetylase 1; Colchicine; Molecular Docking Simulation; Cell Line, Tumor; Cell Proliferation; Apoptosis; Gene Expression Regulation, Neoplastic; Cell Movement
PubMed: 37690423
DOI: 10.1016/j.bbrc.2023.09.006 -
The Laryngoscope Oct 2016To generate novel insights and hypotheses in keloid development from potential master regulators.
OBJECTIVES/HYPOTHESIS
To generate novel insights and hypotheses in keloid development from potential master regulators.
STUDY DESIGN
Prospective cohort.
METHODS
Six fresh keloid and six normal skin samples from 12 anonymous donors were used in a prospective cohort study. Genome-wide profiling was done previously on the cohort using the Infinium HumanMethylation450 BeadChip (Illumina, San Diego, CA). The 190 statistically significant CpG islands between keloid and normal tissue mapped to 152 genes (P < .05). The top 10 statistically significant genes (VAMP5, ACTR3C, GALNT3, KCNAB2, LRRC61, SCML4, SYNGR1, TNS1, PLEKHG5, PPP1R13-α, false discovery rate <.015) were uploaded into the Ingenuity Pathway Analysis software's Causal Network Analysis (QIAGEN, Redwood City, CA). To reflect expected gene expression direction in the context of methylation changes, the inverse of the methylation ratio from keloid versus normal tissue was used for the analysis. Causal Network Analysis identified disease-specific master regulator molecules based on downstream differentially expressed keloid-specific genes and expected directionality of expression (hypermethylated vs. hypomethylated).
RESULTS
Causal Network Analysis software identified four hierarchical networks that included four master regulators (pyroxamide, tributyrin, PRKG2, and PENK) and 19 intermediate regulators.
CONCLUSIONS
Causal Network Analysis of differentiated methylated gene data of keloid versus normal skin demonstrated four causal networks with four master regulators. These hierarchical networks suggest potential driver roles for their downstream keloid gene targets in the pathogenesis of the keloid phenotype, likely triggered due to perturbation/injury to normal tissue.
LEVEL OF EVIDENCE
NA Laryngoscope, 126:E319-E324, 2016.
Topics: Aminopyridines; Case-Control Studies; CpG Islands; Cyclic GMP-Dependent Protein Kinase Type II; DNA Methylation; Enkephalins; Gene Expression; Gene Expression Profiling; Genes, Regulator; Head; Humans; Hydroxamic Acids; Keloid; Neck; Prospective Studies; Protein Precursors; Skin; Triglycerides
PubMed: 26990118
DOI: 10.1002/lary.25958 -
Leukemia Aug 2006
Topics: Aminopyridines; Animals; Antineoplastic Agents; Disease Models, Animal; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Heterologous
PubMed: 16810202
DOI: 10.1038/sj.leu.2404282