-
Antioxidants (Basel, Switzerland) Jun 2021Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to...
Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has provided new hope for refractory AML patients. While generally not efficacious as monotherapy, BH3 mimetics are very effective in combination with chemotherapy agents. With this in mind, we further explored novel BH3 mimetic drug combinations and showed that pimozide cooperates with mTOR inhibitors and BH3 mimetics in AML cells. The three-drug combination was able to reach cells that were not as responsive to single or double drug combinations. In Flt3-internal tandem duplication (ITD)-positive cells, we previously showed pimozide to be highly effective when combined with imipramine blue (IB). Here, we show that Flt3-ITD cells are sensitive to an IB-induced dynamin 1-like (Drp1)-p38-ROS pathway. Pimozide contributes important calcium channel blocker activity converging with IB on mitochondrial oxidative metabolism. Overall, these data support the concept that antioxidants are a double-edged sword. Rationally designed combination therapies have significant promise for further pre-clinical development and may ultimately lead to improved responses.
PubMed: 34203664
DOI: 10.3390/antiox10060956 -
Annals of Nuclear Medicine Feb 2024The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HTR is the newest member of this family and contributes to different...
BACKGROUND
The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HTR is the newest member of this family and contributes to different physiological and pathological processes. As a pathology, glioblastoma multiform (GBM) overexpresses 5-HTR; hence, this study aims to develop radiolabeled aryl piperazine derivatives as 5-HTR imaging agents. METHODS: Compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were radiolabeled with fac-[Tc(CO)(HO)] and Tc(CO)-[6] and Tc(CO)-[7] were obtained with high radiochemical purity (RCP > 94%). The stability of the radiotracers was evaluated in both saline and mouse serum. Specific binding on different cell lines including U-87 MG, MCF-7, SKBR3, and HT-29 was performed. The biodistribution of these radiotracers was evaluated in normal and U-87 MG Xenografted models. Finally, Tc(CO)-[6] and Tc(CO)-[7] were applied for in vivo imaging in U-87 MG Xenografted models.
RESULTS
Specific binding study indicates that Tc(CO)-[6] and Tc(CO)-[7] can recognize 5-HTR of U87-MG cell line. The biodistribution study in normal mice indicates that the brain uptake of Tc(CO)-[6] and Tc(CO)-[7] is the highest at 30 min post-injection (0.8 ± 0.25 and 0.64 ± 0.18%ID/g, respectively). The data of the biodistribution study in the U87-MG xenograft model revealed that these radiotracers could accumulate in the tumor site, and the highest tumor uptake was observed at 60 min post-injection (3.38 ± 0.65 and 3.27 ± 0.5%ID/g, respectively). The injection of pimozide can block the tumor's radiotracer uptake, indicating the binding of these radiotracers to the 5-HTR. The imaging study in the xenograft model also confirms the biodistribution data. The acquired images clearly show the tumor site, and the tumor-to-muscle ratio for Tc(CO)-[6] and Tc(CO)-[7] at 60 min was 3.33 and 3.88, respectively. CONCLUSIONS: Tc(CO)-[6] and Tc(CO)-[7] can visualize tumor in the U87-MG xenograft model due to their affinity toward 5-HTR.
Topics: Mice; Humans; Animals; Serotonin; Tissue Distribution; Neoplasms; Radiopharmaceuticals; Piperazines; Technetium; Cell Line, Tumor
PubMed: 38032496
DOI: 10.1007/s12149-023-01885-2 -
The Journal of Dermatological Treatment May 2022This article introduces to the dermatology provider two medications for the treatment of tardive dyskinesia (TD), which were the first medications approved by the US FDA... (Review)
Review
INTRODUCTION
This article introduces to the dermatology provider two medications for the treatment of tardive dyskinesia (TD), which were the first medications approved by the US FDA specifically for the treatment of TD. In addition to describing these two new medications, this article will also provide a focused review of the pathogenesis of TD, as well as non-FDA-approved treatments, which have been tried prior to the advent of these medications.
METHODS
A PubMed search was conducted and articles were reviewed by the senior authors and included if they were relevant for dermatologists regarding etiology, symptoms, risk, and treatment of TD.
RESULTS
One of the most widely accepted explanations of TD involves the concept of 'dopamine receptor hypersensitivity state.' There are several other less well substantiated proposed pathogenic pathways of TD. The clinical manifestation is characterized by involuntary movements. Prevention includes switching to a 2nd generation agent or using the lowest dose possible for the shortest amount of time. Two new FDA-approved medications for TD are also discussed and reviewed.
CONCLUSION
TD now has FDA-approved medications for treatment. Now, there is even more reason for the dermatologist to have increased confidence when treating delusions of parasitosis (DOP) with antipsychotic agents.
Topics: Antipsychotic Agents; Delusions; Dermatologists; Humans; Tardive Dyskinesia
PubMed: 33781159
DOI: 10.1080/09546634.2021.1892025 -
Drug and Chemical Toxicology Mar 2023Pimozide is an antipsychotic drug used to treat chronic psychosis, such as Tourette's syndrome. Despite its widespread clinical use, pimozide can cause unexpected...
Pimozide is an antipsychotic drug used to treat chronic psychosis, such as Tourette's syndrome. Despite its widespread clinical use, pimozide can cause unexpected adverse effects, including arrhythmias. However, the adverse effects of pimozide on vascular K channels have not yet been determined. Therefore, we investigated the effects of pimozide on voltage-gated K (Kv) channels in rabbit coronary arterial smooth muscle cells. Pimozide concentration-dependently inhibited the Kv currents with an IC value of 1.78 ± 0.17 μM and a Hill coefficient of 0.90 ± 0.05. The inhibitory effect on the Kv current by pimozide was highly voltage-dependent in the voltage range of Kv channel activation, and additive inhibition of the Kv current by pimozide was observed in the full activation voltage range. The decay rate of inactivation was significantly accelerated by pimozide. Pimozide shifted the inactivation curve to a more negative potential. The recovery time constant from inactivation increased in the presence of pimozide. Furthermore, pimozide-induced inhibition of the Kv current was augmented by applying train pulses. Although pretreatment with the Kv2.1 subtype inhibitor guangxitoxin and the Kv7 subtype inhibitor linopirdine did not alter the degree of pimozide-induced inhibition of the Kv currents, pretreatment with the Kv1.5 channel inhibitor DPO-1 reduced the inhibitory effects of pimozide on Kv currents. Pimozide induced membrane depolarization. We conclude that pimozide inhibits Kv currents in voltage-, time-, and use (state)-dependent manners. Furthermore, the major Kv channel target of pimozide is the Kv1.5 channel.
Topics: Animals; Rabbits; Antipsychotic Agents; Pimozide; Potassium Channel Blockers; Muscle, Smooth, Vascular; Potassium Channels, Voltage-Gated; Myocytes, Smooth Muscle
PubMed: 35317682
DOI: 10.1080/01480545.2021.2021932 -
Nature Reviews. Endocrinology Jun 2020
Topics: Diet; Humans; Hyperglycemia; Ketones; Muscle, Skeletal; Obesity; Pimozide
PubMed: 32313125
DOI: 10.1038/s41574-020-0362-8 -
Frontiers in Immunology 2022Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the...
BACKGROUND
Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease.
METHODS
Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of (EC = 0.4 μM) and models, we show that methotrexate is able to inhibit COVID-19 multiple mechanisms.
RESULTS
Our studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals.
CONCLUSIONS
We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.
Topics: Animals; Cricetinae; SARS-CoV-2; COVID-19; Methotrexate; Antiviral Agents; Inflammation; Computational Biology
PubMed: 36618412
DOI: 10.3389/fimmu.2022.1080897 -
Cancer Science Dec 2019ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule....
ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, we generated an ARPC2 knockout DLD-1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system and explored gene signature-based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap-based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex-dependent actin polymerization and inhibited the vinculin-mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2 , ARPC2 and ARPC2 cells, were prepared using ARPC2 knockout cells prepared by gene-editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild-type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide.
Topics: Actin-Related Protein 2-3 Complex; Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Movement; Humans; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Pimozide
PubMed: 31571309
DOI: 10.1111/cas.14205 -
Journal of Hepatology May 2024The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We...
BACKGROUND & AIMS
The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear.
METHODS
To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMOXCT1 (OXCT1 conditional knockout in macrophages) mice.
RESULTS
Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8 T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8 T-cell exhaustion and increasing CD8 T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8 T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC.
CONCLUSIONS
In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.
IMPACT AND IMPLICATIONS
The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.
PubMed: 38759889
DOI: 10.1016/j.jhep.2024.05.007 -
Biotechnology and Applied Biochemistry Oct 2023In spite of the higher nosocomial and community-acquired infections caused by Staphylococcus aureus, emerging drug resistance is a leading cause of increased mortality...
In spite of the higher nosocomial and community-acquired infections caused by Staphylococcus aureus, emerging drug resistance is a leading cause of increased mortality and morbidity associated with the overuse of antimicrobials. It is an emergent need to find out new molecules to combat such infections. In the present study, we analyzed the antibacterial effect of pimozide (PMZ) against gram-positive and gram-negative bacterial strains, including methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) S. aureus. The growth of MSSA and MRSA was completely inhibited at concentrations of 12.5 and 100 μg/mL, respectively, which is referred to as 1× minimum inhibitory concentration (MIC). The cell viability was completely eliminated within 90 min of PMZ treatment (2× MIC) through reactive oxygen species (ROS)-mediated killing without affecting cell membrane permeability. It suppressed α-hemolysin production and biofilm formation of different S. aureus strains by almost 50% at 1× MIC concentration, and was found to detach matured biofilm. PMZ treatment effectively eliminates S. aureus infection in Caenorhabditis elegans and improves its survival by 90% and is found safe to use with no hemolytic effect on human and chicken blood tissues. Taken together, it is concluded that PMZ may turn out to be an effective antibacterial for treating bacterial infections including MSSA and MRSA.
Topics: Humans; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Pimozide; Reactive Oxygen Species; Anti-Bacterial Agents; Staphylococcal Infections; Methicillin; Anti-Infective Agents; Microbial Sensitivity Tests
PubMed: 37000616
DOI: 10.1002/bab.2465 -
Cancers Jan 2022Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings...
Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.
PubMed: 35053502
DOI: 10.3390/cancers14020339