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Frontiers in Molecular Biosciences 2023Breast cancer is the second leading cause of cancer death in women among all cancer types. It is highly heterogeneous in nature, which means that the tumors have...
Breast cancer is the second leading cause of cancer death in women among all cancer types. It is highly heterogeneous in nature, which means that the tumors have different morphologies and there is heterogeneity even among people who have the same type of tumor. Several staging and classifying systems have been developed due to the variability of different types of breast cancer. Due to high heterogeneity, personalized treatment has become a new strategy. Out of all breast cancer subtypes, triple-negative breast cancer (TNBC) comprises ∼10%-15%. TNBC refers to the subtype of breast cancer where cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptors (ERs, PRs, and HERs). Tumors in TNBC have a diverse set of genetic markers and prognostic indicators. We scanned the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases for potential drugs using human breast cancer cell lines and drug sensitivity data. Three different machine-learning approaches were used to evaluate the prediction of six effective drugs against the TNBC cell lines. The top biomarkers were then shortlisted on the basis of their involvement in breast cancer and further subjected to testing for radion resistance using data from the Cleveland database. It was observed that Panobinostat, PLX4720, Lapatinib, Nilotinib, Selumetinib, and Tanespimycin were six effective drugs against the TNBC cell lines. We could identify potential derivates that may be used against approved drugs. Only one biomarker () was sensitive to all six drugs on the shortlist, while two others ( and ) were sensitive to both radiation and drugs. Furthermore, we did not find any radioresistance markers for the TNBC. The proposed biomarkers and drug sensitivity analysis will provide potential candidates for future clinical investigation.
PubMed: 37602329
DOI: 10.3389/fmolb.2023.1215204 -
Cancer Nov 2023Cancer metastasis increases the complexity of the disease and escalates patient mortality. Traditional chemotherapy has been associated with low efficacy and marked side... (Review)
Review
Cancer metastasis increases the complexity of the disease and escalates patient mortality. Traditional chemotherapy has been associated with low efficacy and marked side effects. Studies pivot toward histone deacetylase (HDAC) enzymes and inhibitors because they are critical for chromatin structure, gene regulation, and cellular activities that are linked to metastasis and cancer progression. HDAC inhibitors (HDACi) can alter gene expression patterns and can lead to cell-cycle arrest and apoptosis in neoplastic cells. Several HDACi drugs like vorinostat, romidepsin, panobinostat, and belinostat are approved by the Food and Drug Administration. China and Japan have approved the use of tucidinostat, a new subtype-selective HDACi that inhibits class 1 HDAC1, HDAC2, HDAC3, as well as class 2b HDAC10. These drugs have shown promising results in the treatment of multiple carcinoma including cervical cancer, T-cell lymphoma, brain cancer, and breast cancer. This review highlights the HDACi classes, the mechanism of action of these inhibitors, their preclinical and clinical efficacy, and the latest clinical trials and patents used in cancer therapeutics. Overall, this review focuses on patents and clinical trials data from 2019 onward to give a better viewpoint on current trends in HDACis as chemotherapy agents.
PubMed: 37560925
DOI: 10.1002/cncr.34974 -
NPJ Precision Oncology Aug 2023Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine...
Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine the mechanisms of action of panobinostat, a pan-inhibitor of histone deacetylase (HDAC) and FDA-approved medication for multiple myeloma, in TNBC and to provide a rationale for effective drug combinations against this aggressive disease. RNA sequencing analyses of the claudin-low (CL) TNBC (MDA-MB-231) cells untreated or treated with panobinostat were performed to identify the differentially expressed genes. Adaptive alterations in gene expression were analyzed and validated in additional CL TNBC cells. Tumor xenograft models were used to test the in vivo antitumor activity of panobinostat alone or its combinations with gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). Panobinostat potently inhibited proliferation and induced apoptosis in all TNBC cells tested. However, in CL TNBC cells, this HDAC inhibitor markedly enhanced expression of HER3, which interacted with EGFR to activate both receptors and Akt signaling pathways. Combinations of panobinostat and gefitinib synergistically suppressed CL TNBC cell proliferation and promoted apoptosis in vitro and in vivo. Upregulation of HER3 compromises the efficacy of panobinostat in CL TNBC. Inactivation of HER3 combined with panobinostat represents a practical approach to combat CL TNBC.
PubMed: 37537339
DOI: 10.1038/s41698-023-00422-8 -
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 -
Neuro-oncology Dec 2023Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor...
BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG.
PATIENTS AND METHODS
In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose.
RESULTS
For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT.
CONCLUSIONS
The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.
Topics: Child; Humans; Panobinostat; Diffuse Intrinsic Pontine Glioma; Posterior Leukoencephalopathy Syndrome; Glioma; Thrombocytopenia; Neutropenia; Brain Stem Neoplasms
PubMed: 37526549
DOI: 10.1093/neuonc/noad141 -
Pharmaceutics Jun 2023The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different... (Review)
Review
The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives have drawn considerable interest in the last decade as antitumor agents active against different types of cancers. The research of novel antiproliferative drugs endowed with enhanced efficacy and reduced toxicity led to the approval by U.S. Food and Drug Administration of the indole-based anticancer agents Sunitinib, Nintedanib, Osimertinib, Panobinostat, Alectinib and Anlotinib. Additionally, new drug delivery systems have been developed to protect the active principle from degradation and to direct the drug to the specific site for clinical use, thus reducing its toxicity. In the present work is an updated review of the recently approved indole-based anti-cancer agents and the nanotechnology systems developed for their delivery.
PubMed: 37514002
DOI: 10.3390/pharmaceutics15071815 -
Biomolecules Jul 2023High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but...
High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.
Topics: Humans; Female; Secretome; Ovarian Neoplasms; Epigenesis, Genetic; Diet; Tea; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37509102
DOI: 10.3390/biom13071066 -
Science China. Life Sciences Dec 2023Prime editing (PE) is a recent gene editing technology that can mediate insertions or deletions and all twelve types of base-to-base conversions. However, its low...
Prime editing (PE) is a recent gene editing technology that can mediate insertions or deletions and all twelve types of base-to-base conversions. However, its low efficiency hampers the application in creating novel breeds and biomedical models, especially in pigs and other important farm animals. Here, we demonstrate that the pig genome is editable using the PE system, but the editing efficiency was quite low as expected. Therefore, we aimed to enhance PE efficiency by modulating both exogenous PE tools and endogenous pathways in porcine embryonic fibroblasts (PEFs). First, we modified the pegRNA by extending the duplex length and mutating the fourth thymine in a continuous sequence of thymine bases to cytosine, which significantly enhanced PE efficiency by improving the expression of pegRNA and targeted cleavage. Then, we targeted SAMHD1, a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that impedes the reverse transcription process in retroviruses, and found that treatment with its inhibitor, cephalosporin C zinc salt (CPC), increased PE efficiency up to 29-fold (4-fold on average), presumably by improving the reverse transcription process of Moloney murine leukemia virus reverse transcriptase (M-MLV RT) in the PE system. Moreover, PE efficiency was obviously improved by treatment with a panel of histone deacetylase inhibitors (HDACis). Among the four HDACis tested, panobinostat was the most efficient, with an efficiency up to 122-fold (7-fold on average), partly due to the considerable HDACi-mediated increase in transgene expression. In addition, the synergistic use of the three strategies further enhanced PE efficiency in PEFs. Our study provides novel approaches for optimization of the PE system and broadens the application scope of PE in agriculture and biomedicine.
Topics: Mice; Animals; Swine; Thymine; Animals, Domestic; Transgenes; Agriculture; Cytosine; Gene Editing; Histone Deacetylase Inhibitors; CRISPR-Cas Systems
PubMed: 37505431
DOI: 10.1007/s11427-022-2334-y -
Scientific Reports Jul 2023Drug response prediction is important to establish personalized medicine for cancer therapy. Model construction for predicting drug response (i.e., cell viability...
Drug response prediction is important to establish personalized medicine for cancer therapy. Model construction for predicting drug response (i.e., cell viability half-maximal inhibitory concentration [IC]) of an individual drug by inputting pharmacogenomics in disease models remains critical. Machine learning (ML) has been predominantly applied for prediction, despite the advent of deep learning (DL). Moreover, whether DL or traditional ML models are superior for predicting cell viability IC has to be established. Herein, we constructed ML and DL drug response prediction models for 24 individual drugs and compared the performance of the models by employing gene expression and mutation profiles of cancer cell lines as input. We observed no significant difference in drug response prediction performance between DL and ML models for 24 drugs [root mean squared error (RMSE) ranging from 0.284 to 3.563 for DL and from 0.274 to 2.697 for ML; R ranging from -7.405 to 0.331 for DL and from -8.113 to 0.470 for ML]. Among the 24 individual drugs, the ridge model of panobinostat exhibited the best performance (R 0.470 and RMSE 0.623). Thus, we selected the ridge model of panobinostat for further application of explainable artificial intelligence (XAI). Using XAI, we further identified important genomic features for panobinostat response prediction in the ridge model, suggesting the genomic features of 22 genes. Based on our findings, results for an individual drug employing both DL and ML models were comparable. Our study confirms the applicability of drug response prediction models for individual drugs.
Topics: Artificial Intelligence; Panobinostat; Machine Learning; Genomics; Cell Line, Tumor
PubMed: 37488424
DOI: 10.1038/s41598-023-39179-2 -
CNS Neuroscience & Therapeutics Feb 2024PSMD family members, as important components of the 26S proteasome, are well known to be involved in protein degradation. However, their role in glioblastoma (GBM) has...
AIMS
PSMD family members, as important components of the 26S proteasome, are well known to be involved in protein degradation. However, their role in glioblastoma (GBM) has not been rigorously investigated. We aimed to perform systematic analysis of the expression signature, prognostic significance and functions of PSMD family genes in GBM to reveal potential prognostic markers and new therapeutic targets among PSMD family members.
METHODS
In this study, we systemically analyzed PSMD family members in terms of their expression profiles, prognostic implications, DNA methylation levels, and genetic alterations; the relationships between their expression levels and immune infiltration and drug sensitivity; and their potential functional enrichment in GBM through bioinformatics assessment. Moreover, in vitro and in vivo experiments were used to validate the biological functions of PSMD9 and its targeted therapeutic effect in GBM.
RESULTS
The mRNA levels of PSMD5/8/9/10/11/13/14 were higher in GBM than in normal brain tissues, and the mRNA levels of PSMD1/4/5/8/9/11/12 were higher in high-grade glioma (WHO grade III & IV) than in low-grade glioma (WHO grade II). High mRNA expression of PSMD2/6/8/9/12/13/14 and low mRNA expression of PSMD7 were associated with poor overall survival (OS). Multivariate Cox regression analysis identified PSMD2/5/6/8/9/10/11/12 as independent prognostic factors for OS prediction. In addition, the protein-protein interaction network and gene set enrichment analysis results suggested that PSMD family members and their interacting molecules were involved in the regulation of the cell cycle, cell invasion and migration, and other biological processes in GBM. In addition, knockdown of PSMD9 inhibited cell proliferation, invasion and migration and induced G2/M cell cycle arrest in LN229 and A172 GBM cells. Moreover, PSMD9 promoted the malignant progression of GBM in vivo. GBM cell lines with high PSMD9 expression were more resistant to panobinostat, a potent deacetylase inhibitor, than those with low PSMD9 expression. In vitro and in vivo experiments further validated that PSMD9 overexpression rescued the GBM inhibitory effect of panobinostat.
CONCLUSION
This study provides new insights into the value of the PSMD family in human GBM diagnosis and prognosis evaluation, and we further identified PSMD9 as a potential therapeutic target. These findings may lead to the development of effective therapeutic strategies for GBM.
Topics: Humans; Glioblastoma; Panobinostat; Brain Neoplasms; Cell Line, Tumor; Glioma; Prognosis; Transcription Factors; RNA, Messenger; Gene Expression Regulation, Neoplastic; Proteasome Endopeptidase Complex
PubMed: 37485655
DOI: 10.1111/cns.14366