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Acta Pharmaceutica Sinica. B Jul 2022Cancer, which is the uncontrolled growth of cells, is the second leading cause of death after heart disease. Targeting drugs, especially to specific genes and proteins... (Review)
Review
Cancer, which is the uncontrolled growth of cells, is the second leading cause of death after heart disease. Targeting drugs, especially to specific genes and proteins involved in growth and survival of cancer cells, is the prime need of research world-wide. Indole moiety, which is a combination of aromatic-heterocyclic compounds, is a constructive scaffold for the development of novel leads. Owing to its bioavailability, high unique chemical properties and significant pharmacological behaviours, indole is considered as the most inquisitive scaffold for anticancer drug research. This is illustrated by the fact that the U.S. Food and Drug Administration (FDA) has recently approved several indole-based anticancer agents such as panobinostat, alectinib, sunitinib, osimertinib, anlotinib and nintedanib for clinical use. Furthermore, hundreds of studies on the synthesis and activity of the indole ring have been published in the last three years. Taking into account the facts stated above, we have presented the most recent advances in medicinal chemistry of indole derivatives, encompassing hot articles published between 2018 and 2021 in anticancer drug research. The recent advances made towards the synthesis of promising indole-based anticancer compounds that may act various targets such as topoisomerase, tubulin, apoptosis, aromatase, kinases, etc., have been discussed. This review also summarizes some of the recent efficient green chemical synthesis for indole rings using various catalysts for the period during 2018-2021. The review also covers the synthesis, structure‒activity relationship, and mechanism by which these leads have demonstrated improved and promising anticancer activity. Indole molecules under clinical and preclinical stages are classified into groups based on their cancer targets and presented in tabular form, along with their mechanism of action. The goal of this review article is to point the way for medicinal chemists to design and develop effective indole-based anticancer agents.
PubMed: 35865090
DOI: 10.1016/j.apsb.2022.03.021 -
ChemMedChem Dec 2021We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the...
We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.
Topics: Antineoplastic Agents; Apoptosis; Cell Death; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Molecular Structure; Panobinostat; Prodrugs; Structure-Activity Relationship
PubMed: 34259396
DOI: 10.1002/cmdc.202100403 -
Pharmaceuticals (Basel, Switzerland) Feb 2024Triple-negative breast cancer (TNBC) poses a therapeutic challenge due to its aggressive nature and lack of targeted therapies. Epigenetic modifications contribute to...
Triple-negative breast cancer (TNBC) poses a therapeutic challenge due to its aggressive nature and lack of targeted therapies. Epigenetic modifications contribute to TNBC tumorigenesis and drug resistance, offering potential therapeutic targets. Recent advancements in three-dimensional (3D) organoid cultures, enabling precise drug screening, hold immense promise for identifying novel compounds targeting TNBC. In this study, we established two patient-derived TNBC organoids and implemented a high-throughput drug screening system using these organoids and two TNBC cell lines. Screening a library of 169 epigenetic compounds, we found that organoid-based systems offer remarkable precision in drug response assessment compared to cell-based models. The top 30 compounds showing the highest drug sensitivity in the initial screening were further assessed in a secondary screen. Four compounds, panobinostat, pacritinib, TAK-901, and JIB-04, targeting histone deacetylase, JAK/STAT, histone demethylases, and aurora kinase pathways, respectively, exhibited potent anti-tumor activity in TNBC organoids, surpassing the effect of paclitaxel. Our study highlights the potential of these novel epigenetic drugs as effective therapeutic agents for TNBC and demonstrates the valuable role of patient-derived organoids in advancing drug discovery.
PubMed: 38399440
DOI: 10.3390/ph17020225 -
Frontiers in Microbiology 2020Invasive fungal infections are an emerging problem worldwide, which bring huge health challenges. , the most common opportunistic fungal pathogen, can cause bloodstream...
Invasive fungal infections are an emerging problem worldwide, which bring huge health challenges. , the most common opportunistic fungal pathogen, can cause bloodstream infections with high mortality in susceptible hosts. At present, available antifungal agents used in clinical practice are limited, and most of them also have some serious adverse effects. The emergence of drug resistance because of the wide use of antifungal agents is a new limitation to successful patient therapy. Drug combination therapy is increasingly becoming a way to enhance antifungal efficacy, and reduce drug resistance and potential toxicity. Panobinostat, as a pan-histone deacetylase inhibitor, has been approved by the United States Food and Drug Administration as novel antitumor agents. In this study, the antifungal effects and mechanisms of panobinostat combined with fluconazole (FLC) against were explored for the first time. The results indicated that panobinostat could work synergistically with FLC against resistant , the minimal inhibitory concentration (MIC) of panobinostat could decrease from 128 to 0.5-2 μg/ml and the MIC of FLC could decrease from >512 to 0.25-0.5 μg/ml, and the fractional inhibitory concentration index (FICI) value ranged from 0.0024 to 0.0166. It was not only synergized against planktonic cells but also against biofilms performed ≤8 h when panobinostat is combined with fluconazole; the sessile MIC (sMIC) of panobinostat could decrease from >128 to 0.5-8 μg/ml and the sMIC of FLC from >1024 to 0.5-2 μg/ml, and the FICI value was <0.5. The infection model was used to evaluate the effect of the drug combination, and the result showed that the survival rate could be improved obviously. Finally, we explored the synergistic mechanisms of the drug combination. The hyphal growth, which plays roles in drug resistance, was found to be inhibited, and metacaspase which is related to cell apoptosis was activated ( < 0.01), whereas the synergistic effects were proven not to be related to the efflux pumps ( > 0.05). These findings might provide novel insights into the antifungal drug discovery and the treatment of candidiasis caused by .
PubMed: 32765454
DOI: 10.3389/fmicb.2020.01584 -
Journal of Experimental & Clinical... Nov 2022Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor clinical outcomes and respond poorly to current therapies....
BACKGROUND
Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor clinical outcomes and respond poorly to current therapies. Epigenetic deregulation is very common in MYC-driven MB. The bromodomain extra-terminal (BET) proteins and histone deacetylases (HDACs) are epigenetic regulators of MYC transcription and its associated tumorigenic programs. This study aimed to investigate the therapeutic potential of inhibiting the BET proteins and HDACs together in MB.
METHODS
Using clinically relevant BET inhibitors (JQ1 or OTX015) and a pan-HDAC inhibitor (panobinostat), we evaluated the effects of combined inhibition on cell growth/survival in MYC-amplified MB cell lines and xenografts and examined underlying molecular mechanism(s).
RESULTS
Co-treatment of JQ1 or OTX015 with panobinostat synergistically suppressed growth/survival of MYC-amplified MB cells by inducing G2 cell cycle arrest and apoptosis. Mechanistic investigation using RNA-seq revealed that co-treatment of JQ1 with panobinostat synergistically modulated global gene expression including MYC/HDAC targets. SYK and MSI1 oncogenes were among the top 50 genes synergistically downregulated by JQ1 and panobinostat. RT-PCR and western blot analyses confirmed that JQ1 and panobinostat synergistically inhibited the mRNA and protein expression of MSI1/SYK along with MYC expression. Reduced SYK/MSI expression after BET (specifically, BRD4) gene-knockdown further confirmed the epigenetic regulation of SYK and MSI1 genes. In addition, the combination of OTX015 and panobinostat significantly inhibited tumor growth in MYC-amplified MB xenografted mice by downregulating expression of MYC, compared to single-agent therapy.
CONCLUSIONS
Together, our findings demonstrated that dual-inhibition of BET and HDAC proteins of the epigenetic pathway can be a novel therapeutic approach against MYC-driven MB.
Topics: Humans; Mice; Animals; Medulloblastoma; Histone Deacetylases; Nuclear Proteins; Panobinostat; Azepines; Epigenesis, Genetic; Cell Cycle Proteins; Cell Line, Tumor; Transcription Factors; Triazoles; Apoptosis; Cell Proliferation; Cerebellar Neoplasms; Proto-Oncogene Proteins c-myc
PubMed: 36357906
DOI: 10.1186/s13046-022-02530-y -
Cancers Oct 2020Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major...
Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents.
PubMed: 33050470
DOI: 10.3390/cancers12102903 -
The Oncologist Aug 2019NUT carcinoma is a rare aggressive disease caused by fusion, and upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological...
BACKGROUND
NUT carcinoma is a rare aggressive disease caused by fusion, and upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines.
MATERIALS AND METHODS
Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907).
RESULTS
Primary tumor sites included head and neck ( = 9) and lung ( = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for in NUT carcinoma cells. Panobinostat (IC, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC, 3.7-8.2 nmol/L), also showed remarkable efficacies.
CONCLUSION
East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment.
IMPLICATIONS FOR PRACTICE
NUT carcinoma (NC) is a disease caused by fusion leading to upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.
Topics: Adolescent; Adult; Aged; Cell Line, Tumor; Cell Proliferation; Child; Female; Head and Neck Neoplasms; Heterocyclic Compounds, 2-Ring; Histone Deacetylase Inhibitors; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Morpholines; Nuclear Proteins; Oncogene Proteins, Fusion; Phosphatidylinositol 3-Kinases; Piperazines; Proteins; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyridazines; Pyrimidines; Young Adult
PubMed: 30696721
DOI: 10.1634/theoncologist.2018-0477 -
Frontiers in Cell and Developmental... 2020Epigenetic modulation, including acetylation, methylation, phosphorylation, and ubiquitination, plays a pivotal role in regulation of gene expression. Histone... (Review)
Review
Epigenetic modulation, including acetylation, methylation, phosphorylation, and ubiquitination, plays a pivotal role in regulation of gene expression. Histone acetylation-a balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs)-is one of the key epigenetic events. Our understanding of the role of HDACs in cancer is evolving. A number of HDAC isoenzymes are overexpressed in a variety of malignancies. Aberrant histone acetylation is associated with dysregulation of tumor suppressor genes leading to development of several solid tumors and hematologic malignancies. Pre-clinical studies have demonstrated that HDAC-1 gene expression is associated with lung cancer progression. Histone hypoacetylation is associated with more aggressive phenotype in adenocarcinoma of the lung. HDAC inhibitors (HDACi) have pleiotropic cellular effects and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest, inhibit angiogenesis, and inhibit transition to a mesenchymal phenotype. Consequently, treatment with HDACi has shown anti-proliferative activity in non-small cell lung cancer (NSCLC) cell lines. Despite promising results in pre-clinical studies, HDACi have shown only modest single agent activity in lung cancer clinical trials. HDAC activation has been implicated as one of the mechanisms causing resistance to chemotherapy, molecularly targeted therapy, and immune checkpoint inhibition. Therefore, there is a growing interest in combining HDACi with these agents to enhance their efficacy or reverse resistance. In this paper, we review the available preclinical and clinical evidence for the use of HDACi in NSCLC. We also review the challenges precluding widespread clinical utility of HDACi as a cancer therapy and future directions.
PubMed: 33163495
DOI: 10.3389/fcell.2020.582370 -
Clinical and Experimental Immunology Aug 2022Sarcoma is a rare and heterogeneous class of mesenchymal malignancies with poor prognosis. Panobinostat (LBH589) as one of histone deacetylase (HDAC) inhibitors has...
Sarcoma is a rare and heterogeneous class of mesenchymal malignancies with poor prognosis. Panobinostat (LBH589) as one of histone deacetylase (HDAC) inhibitors has demonstrated anti-tumor activity in patients with sarcoma, but its mechanisms remains unclear. Here, we found that LBH589 alone inhibited the proliferation and colony formation of soft tissue sarcoma (STS) cell lines. Transcriptome analysis showed that treatment with LBH589 augmented the NK cell-mediated cytotoxicity. Quantitative real-time PCR and flow cytometric analysis (FACS) further confirmed that LBH589 increased the expression of NKG2D ligands MICA/MICB. Mechanistically, LBH589 activated the Wnt/β-catenin pathway by upregulating the histone acetylation in β-catenin promoter. In vitro co-culture experiments and in vivo animal experiments showed that LBH589 increased the cytotoxicity of natural killer (NK) cells while Wnt/β-catenin inhibitor decreased the effects. Our findings suggest that LBH589 facilitates the anti-tumor effect of NK cells, highlights LBH589 an effective assistance drug in NK cell-based immunotherapies.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Histone Deacetylase Inhibitors; Hydroxamic Acids; Killer Cells, Natural; Panobinostat; Sarcoma; beta Catenin
PubMed: 35867577
DOI: 10.1093/cei/uxac068 -
Blood Advances Apr 2022Epigenetic alterations, including histone acetylation, contribute to the malignant transformation of hematopoietic cells and disease progression, as well as the...
Epigenetic alterations, including histone acetylation, contribute to the malignant transformation of hematopoietic cells and disease progression, as well as the emergence of chemotherapy resistance. Targeting histone acetylation provides new strategies for the treatment of cancers. As a pan-histone deacetylase inhibitor, panobinostat has been approved by the US Food and Drug Administration for the treatment of multiple myeloma and has shown promising antileukemia effects in acute lymphoblastic leukemia (ALL). However, the underlying drug resistance mechanism in ALL remains largely unknown. Using genome-wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas)9 (CRISPR/Cas9) screening, we identified mitochondrial activity as the driver of panobinostat resistance in ALL. Mechanistically, ectopic SIRT1 expression activated mitochondrial activity and sensitized ALL to panobinostat through activating mitochondria-related apoptosis pathway. Meanwhile, the transcription level of SIRT1 was significantly associated with panobinostat sensitivity across diverse tumor types and thus could be a potential biomarker of panobinostat response in cancers. Our data suggest that patients with higher SIRT1 expression in cancer cells might benefit from panobinostat treatment, supporting the implementation of combinatorial therapy with SIRT1 or mitochondrial activators to overcome panobinostat resistance.
Topics: Apoptosis; CRISPR-Cas Systems; Histones; Humans; Panobinostat; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sirtuin 1; United States
PubMed: 35192680
DOI: 10.1182/bloodadvances.2021006152