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Biomacromolecules Dec 2023Aiming toward the development of tailored carrier materials for the cytostatics panobinostat and imatinib, an amphiphilic block copolymer composed of...
Aiming toward the development of tailored carrier materials for the cytostatics panobinostat and imatinib, an amphiphilic block copolymer composed of poly(2-ethyl-2-oxazoline) and a degradable poly(2-(3-phenylpropyl)-2-oxazoline) analogue () was synthesized a postpolymerization synthesis route based on reacylation of oxidized linear poly(ethylene imine). The obtained was found to readily self-assemble into well-defined micelles with a critical micelle concentration of 1 μg mL. The incubation of HUVEC cells with the blank micelles revealed their excellent cytocompatibility (up to 2 mg mL), thus confirming the polymers' suitability for potential drug delivery application. Subsequently, the encapsulation of the two cytostatics, panobinostat and imatinib, into the micelles was successfully demonstrated ( ≈ 80 nm, PDI ≈ 0.16), whereby the well-defined nature of the micelle was maintained upon extended incubation at 37 °C (36 h) and storage at 4 °C (1 month). Labeling of the micelles with Alexa Fluor 594 and Alexa Fluor 647, which form a Förster resonance energy transfer (FRET) pair, indicated the stability of loaded micelles upon dilution until the CMC. Finally, the cytotoxicity of the loaded micelles was investigated against three different cell lines: Medulloblastoma cell lines ONS-76 and DAOY as well as the glioblastoma cell line U87MG. While the panobinostat-loaded micelles displayed similar cytotoxicity compared to the pure drug in the cell lines, imatinib-loaded micelles were found to be more potent compared to the pristine drug, as significantly higher cytotoxicity was observed across all three cell lines.
Topics: Micelles; Panobinostat; Imatinib Mesylate; Drug Carriers; Glycine; Polymers; Polyethylene Glycols
PubMed: 37987713
DOI: 10.1021/acs.biomac.3c00934 -
Acta Neuropathologica Communications Apr 2024We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic...
We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.
Topics: Humans; Panobinostat; NF-E2-Related Factor 2; Neuroendocrine Tumors; Histone Deacetylase Inhibitors; Signal Transduction; Pituitary Neoplasms
PubMed: 38637883
DOI: 10.1186/s40478-024-01775-2 -
Cancer Medicine Dec 2023Thyroid hormone receptor interacting protein 13 (Trip13) is an AAA-ATPase that regulates the assembly or disassembly protein complexes and mediates Double-strand breaks...
BACKGROUND
Thyroid hormone receptor interacting protein 13 (Trip13) is an AAA-ATPase that regulates the assembly or disassembly protein complexes and mediates Double-strand breaks (DSBs) repair. Overexpression of Trip13 has been detected in many cancers and is associated with myeloma progression, disease relapse and poor prognosis inmultiple myeloma (MM).
METHODS
We have identified a small molecular, TI17, through a parallel compound-centric approach, which specifically targets Trip13. To identify whether TI17 targeted Trip13, pull-down and nuclear magnetic resonance spectroscopy (NMR) assays were performed. Cell counting kit-8, clone formation, apoptosis and cell cycle assays were applied to investigate the effects of TI17. We also utilized a mouse model to investigate the effects of TI17 in vivo.
RESULTS
TI17 effectively inhibited the proliferation of MM cells, and induced the cycle arrest and apoptosis of MM cells. Furthermore, treatment with TI17 abrogates tumor growth and has no apparent side effects in mouse xenograft models. TI17 specifically impaired Trip13 function of DSBs repair and enhanced DNA damage responses in MM. Combining with melphalan or HDAC inhibitor panobinostat triggers synergistic anti-MM effect.
CONCLUSIONS
Our study suggests that TI17 could be acted as a specific inhibitor of Trip13 and supports a preclinical proof of concept for therapeutic targeting of Trip13 in MM.
Topics: Humans; Animals; Mice; Multiple Myeloma; DNA Breaks, Double-Stranded; Neoplasm Recurrence, Local; Cell Cycle Proteins; DNA Repair; Cell Cycle
PubMed: 37942576
DOI: 10.1002/cam4.6706 -
Neuro-oncology Advances 2023Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the...
BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB opening, allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect.
METHODS
Mice were orthotopically injected with a patient-derived diffuse midline glioma (DMG) cell line, BT245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa peak negative pressure, 1 Hz pulse repetition frequency, 10-ms pulse length, 3 min treatment time)/(25 µL/kg, i.v.) targeting to the tumor location.
RESULTS
In animals receiving panobinostat (10 mg/kg, i.p.) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, without significant increase of the drug in the forebrain. In mice receiving 3 weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes ( = .01). Furthermore, we showed the first survival benefit from FUS/MB improved delivery increasing the mean survival from 21 to 31 days ( < .0001).
CONCLUSIONS
Our study demonstrates that FUS-mediated BBB disruption can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.
PubMed: 37795179
DOI: 10.1093/noajnl/vdad111 -
Rapid Communications in Mass... Jan 2024Thermal proteome profiling (TPP) has been widely used for the identification of drug targets for several years, and TMTpro-16plex has recently been evaluated for TPP of...
RATIONALE
Thermal proteome profiling (TPP) has been widely used for the identification of drug targets for several years, and TMTpro-16plex has recently been evaluated for TPP of vehicle- and drug-treated samples in a single labeling process to reduce missing values and save instrument time. A novel isobaric labeling reagent, IBT-16plex, was developed with slightly better performance in protein identification and quantification than the commercially available TMTpro-16plex.
METHODS
In this study, we applied the newly developed IBT-16plex for target identification of methotrexate and panobinostat using TPP.
RESULTS
The known targets of these two drugs were successfully identified with elevated melting temperatures, and some known off-targets and potential new off-targets were also identified.
CONCLUSIONS
IBT-16plex can be a cost-effective replacement for TMTpro-16plex for TPP applications.
Topics: Proteome; Proteomics; Panobinostat
PubMed: 38073198
DOI: 10.1002/rcm.9673 -
Journal of Chemical Information and... Feb 2024Ovarian cancer (OC) is a highly heterogeneous disease, with patients at different tumor staging having different survival times. Metabolic reprogramming is one of the...
Ovarian cancer (OC) is a highly heterogeneous disease, with patients at different tumor staging having different survival times. Metabolic reprogramming is one of the key hallmarks of cancer; however, the significance of metabolism-related genes in the prognosis and therapy outcomes of OC is unclear. In this study, we used weighted gene coexpression network analysis and differential expression analysis to screen for metabolism-related genes associated with tumor staging. We constructed the metabolism-related gene prognostic index (MRGPI), which demonstrated a stable prognostic value across multiple clinical trial end points and multiple validation cohorts. The MRGPI population had its distinct molecular features, mutational characteristics, and immune phenotypes. In addition, we investigated the response to immunotherapy in MRGPI subgroups and found that patients with low MRGPI were prone to benefit from anti-PD-1 checkpoint blockade therapy and exhibited a delayed treatment effect. Meanwhile, we identified four candidate therapeutic drugs (ABT-737, crizotinib, panobinostat, and regorafenib) for patients with high MRGPI, and we evaluated the pharmacokinetics and safety of the candidate drugs. In summary, the MRGPI was a robust clinical feature that could predict patient prognosis, immunotherapy response, and candidate drugs, facilitating clinical decision making and therapeutic strategy of OC.
Topics: Humans; Female; Prognosis; Immunotherapy; Ovarian Neoplasms; Metabolic Reprogramming; Mutation
PubMed: 38238993
DOI: 10.1021/acs.jcim.3c01473 -
International Journal of Biological... 2023Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited...
Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited and the underlying mechanism remains poorly understood. Targeting histone modifications is an emerging strategy for cancer therapy, but little is known regarding the role of heat stress in altering these modifications. Here, we report that heat shock inhibits H3K9 acetylation (H3K9ac) via histone deacetylase 6 (HDAC6) regulation. Heat shock inhibits the interaction between HDAC6 and heat shock protein 90 (HSP90), enhances nuclear localization of HDAC6, and promotes HDAC6 phosphorylation, which is regulated by protein phosphatase 2A (PP2A). Combining hyperthermia with HDAC inhibitors vorinostat or panobinostat leads to better anti-cancer effects compared to monotherapy. and as genes affected by heat-induced inhibition of H3K9ac, and combining them with hyperthermia can better induce apoptosis in tumor cells. This study reveals previously unknown mechanisms of H3K9ac decreased by heat shock in cancer cells and highlights a potential combinational therapy involving hyperthermia and targeting of these new mechanisms.
Topics: Kelch-Like ECH-Associated Protein 1; Histone Deacetylases; Acetylation; Hydroxamic Acids; NF-E2-Related Factor 2; Heat-Shock Response; Hyperthermia, Induced; Neoplasms
PubMed: 37781518
DOI: 10.7150/ijbs.86384 -
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 -
Molecular Cancer Therapeutics Apr 2024Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the...
Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic. To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA-sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril. As romidepsin has a thiol as the zinc-binding moiety, we hypothesized that METTL7A could inactivate romidepsin and other thiol-based HDACis via methylation of the thiol group. We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.
Topics: Humans; Histone Deacetylase Inhibitors; Methyltransferases; Neoplasms; Panobinostat; Zinc
PubMed: 38151817
DOI: 10.1158/1535-7163.MCT-23-0144 -
The Egyptian Journal of Immunology Oct 2023Although many drugs are available for childhood systemic lupus erythematosus (SLE) treatment, the adverse effects and poor response in some cases make it crucial to find...
Although many drugs are available for childhood systemic lupus erythematosus (SLE) treatment, the adverse effects and poor response in some cases make it crucial to find new drugs targeting various pathways in disease pathogenesis to improve overall outcomes. This study aimed to (i) investigate the effect of Panobinostat on cultured lymphocytes obtained from children with active SLE and (ii) to compare that effect with standard drugs used in SLE, such as Prednisone and hydroxychloroquine. The study included 24 SLE active patients, divided into four equal groups. Lymphocytes were isolated from blood samples of the study patients. According to the study group, cells were treated with either Panobinostat, Prednisolone, hydroxychloroquine, or not treated (control group). After cell culture, the response of lymphocytes upon drug treatment was analyzed in terms of the production of anti-dsDNA antibodies and levels of apoptosis as detected by flow cytometry using annexin V and propidium iodide (PI) staining. The Panobinostat group showed a significant decrease in the viable cell count (p < 0.001). Both Prednisone and hydroxychloroquine decreased anti-dsDNA expression more than the Panobinostat and control groups (p < 0.001 for both). PI was higher in the Prednisone group, and Annexin V was higher in the Panobinostat group compared to other groups; however, their increase did not reach statistically significant levels (p= 0.12 and 0.85, respectively). This is the first study of the Panobinostat effect on cultured lymphocytes of SLE. In conclusion, Panobinostat could be a prospective treatment for B-cell-driven autoimmune diseases such as SLE. However, its effect on autoantibodies levels and different clinical features of SLE still need a thorough evaluation.
Topics: Humans; Child; Hydroxychloroquine; Panobinostat; Prednisone; Annexin A5; Lupus Erythematosus, Systemic; Lymphocytes
PubMed: 37801033
DOI: No ID Found