ABSTRACT
BACKGROUND: Numerous studies have proven the efficacy and safety of natural products, and are widely used as attractive cancer treatments. The investigation of effective natural products for improving cancer treatment is a promising strategy. Combination treatment with radiosensitizers and radiotherapy (RT) is considered necessary for therapeutic improvement in head and neck squamous cell carcinoma(HNSCC). OBJECTIVE: This study aims to investigate whether Ephedra sinica (ES) extract could induce selective cell death in cancer cells and serve as a radiosensitizer for HNSCC. METHODS: HNSCC cells were pretreated with ES extract before radiation, and the radiosensitizing activity was assessed using a colony formation assay. Radiation-induced cell death was evaluated using an annexinV-FITC assay. Western blotting was performed to confirm cell death-related gene expression, including apoptosis and necrosis markers. RESULTS: ES extract significantly inhibited HNSCC cell viability (FaDu and SNU1076), while having minimal effect on normal HaCaT cells. When HNSCC cells were irradiated with 2, 4, or 8 Gy and cultured with ES extract (25 µg/mL), they exhibited increased radiation sensitivity compared to non-treated cells. The combination of ES extract and radiation resulted in increased cell death compared to non-treated, ES-treated, or irradiated cells. The apoptosis marker BAX and necrosis marker p-MLKL expression levels were also elevated following the combination treatment. CONCLUSION: ES extract demonstrated significant cytotoxic potential in HNSCC cells without affecting normal cells. It enhanced the radiosensitivity of HNSCC cells by upregulating BAX and p-MLKL expression, leading to increased cell death. These results suggest ES extract exhibits a potential radiosensitizing capacity in HNSCC.
Subject(s)
Biological Products , Carcinoma, Squamous Cell , Ephedra sinica , Head and Neck Neoplasms , Radiation-Sensitizing Agents , Humans , Squamous Cell Carcinoma of Head and Neck/drug therapy , bcl-2-Associated X Protein/genetics , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Cell Line, Tumor , Cell Death , Apoptosis , Radiation-Sensitizing Agents/pharmacology , Radiation-Sensitizing Agents/therapeutic use , Necrosis , Biological Products/pharmacology , Protein Kinases/pharmacology , Protein Kinases/therapeutic useABSTRACT
BACKGROUND AND OBJECTIVE: Parkinson's Disease (PD), a common neurodegenerative disorder and one of the major current challenges in neuroscience and pharmacology, may potentially be tackled by the modern AI techniques employed in drug discovery based on molecular property prediction. The aim of our study was to explore the application of a machine learning setup for the identification of the best potential drug candidates among FDA approved drugs, based on their predicted PINK1 expression-enhancing activity. METHODS: Our study relies on supervised machine learning paradigm exploiting in vitro data and utilizing the scaffold splits methodology in order to assess model's capability to extract molecular patterns and generalize from them to new, unseen molecular representations. Models' predictions are combined in a meta-ensemble setup for finding new pharmacotherapies based on the predicted expression of PINK1. RESULTS: The proposed machine learning setup can be used for discovering new drugs for PD based on the predicted increase of expression of PINK1. Our study identified nitazoxanide as well as representatives of imidazolidines, trifluoromethylbenzenes, anilides, nitriles, stilbenes and steroid esters as the best potential drug candidates for PD with PINK1 expression-enhancing activity on or inside the cell's mitochondria. CONCLUSIONS: The applied methodology allows to reveal new potential drug candidates against PD. Next to novel indications, it allows also to confirm the utility of already known antiparkinson drugs, in the new context of PINK1 expression, and indicates the potential for simultaneous utilization of different mechanisms of action.
Subject(s)
Parkinson Disease , Humans , Parkinson Disease/drug therapy , Drug Repositioning , Mitochondria/metabolism , Antiparkinson Agents/pharmacology , Protein Kinases/metabolism , Protein Kinases/therapeutic useABSTRACT
Gulf War Illness (GWI) is an unrelenting multi-symptom illness with chronic central nervous system and peripheral pathology affecting veterans from the 1991 Gulf War and for which effective treatment is lacking. An increasing number of studies indicate that persistent neuroinflammation is likely the underlying cause of cognitive and mood dysfunction that affects veterans with GWI. We have previously reported that fingolimod, a drug approved for the treatment of relapsing-remitting multiple sclerosis, decreases neuroinflammation and improves cognition in a mouse model of Alzheimer's disease. In this study, we investigated the effect of fingolimod treatment on cognition and neuroinflammation in a mouse model of GWI. We exposed C57BL/6 J male mice to GWI-related chemicals pyridostigmine bromide, DEET, and permethrin, and to mild restraint stress for 28 days (GWI mice). Control mice were exposed to the chemicals' vehicle only. Starting 3 months post-exposure, half of the GWI mice and control mice were orally treated with fingolimod (1 mg/kg/day) for 1 month, and the other half were left untreated. Decreased memory on the Morris water maze test was detected in GWI mice compared to control mice and was reversed by fingolimod treatment. Immunohistochemical analysis of brain sections with antibodies to Iba1 and GFAP revealed that GWI mice had increased microglia activation in the hippocampal dentate gyrus, but no difference in reactive astrocytes was detected. The increased activation of microglia in GWI mice was decreased to the level in control mice by treatment with fingolimod. No effect of fingolimod treatment on gliosis in control mice was detected. To explore the signaling pathways by which decreased memory and increased neuroinflammation in GWI may be protected by fingolimod, we investigated the involvement of the inflammatory signaling pathways of protein kinase R (PKR) in the cerebral cortex of these mice. We found increased phosphorylation of PKR in the brain of GWI mice compared to controls, as well as increased phosphorylation of its most recognized downstream effectors: the α subunit of eukaryotic initiation factor 2 (eIF2α), IκB kinase (IKK), and the p65 subunit of nuclear factor-κB (NFκB-p65). Furthermore, we found that the increased phosphorylation level of these three proteins were suppressed in GWI mice treated with fingolimod. These results suggest that activation of PKR and NFκB signaling may be important for the regulation of cognition and neuroinflammation in the GWI condition and that fingolimod, a drug already approved for human use, may be a potential candidate for the treatment of GWI.
Subject(s)
Fingolimod Hydrochloride , Persian Gulf Syndrome , Animals , Male , Mice , Amnesia/metabolism , Disease Models, Animal , Fingolimod Hydrochloride/therapeutic use , Fingolimod Hydrochloride/metabolism , Fingolimod Hydrochloride/pharmacology , Gulf War , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Memory Disorders/metabolism , Mice, Inbred C57BL , Microglia , Neuroinflammatory Diseases , NF-kappa B/metabolism , Persian Gulf Syndrome/chemically induced , Persian Gulf Syndrome/drug therapy , Persian Gulf Syndrome/metabolism , Protein Kinases/metabolism , Protein Kinases/pharmacology , Protein Kinases/therapeutic use , Pyridostigmine Bromide/therapeutic use , Pyridostigmine Bromide/pharmacologyABSTRACT
Environmental exposure to crystalline silica (CS) can lead to silicosis. Alveolar macrophages (AMs) play a crucial role in the pathogenesis of silicosis. Previously, we demonstrated that enhancing AMs mitophagy exerted protective effects on silicosis with a restrained inflammatory response. However, the exact molecular mechanisms are elusive. Pyroptosis and mitophagy are two different biological processes that determine cell fate. Exploring whether there were interactions or balances between these two processes in AMs would provide new insight into treating silicosis. Here we reported that crystalline silica induced pyroptosis in silicotic lungs and AMs with apparent mitochondria injury. Notably, we identified a reciprocal inhibitory effect between mitophagy and pyroptosis cascades in AMs. By enhancing or diminishing mitophagy, we demonstrated that PINK1-mediated mitophagy helped clear damaged mitochondria to negatively regulate CS-induced pyroptosis. While constraining pyroptosis cascades by NLRP3, Caspase1, and GSDMD inhibitors, respectively, displayed enhanced PINK1-dependent mitophagy with lessened CS-injured mitochondria. These observed effects were echoed in the mice with enhanced mitophagy. Therapeutically, we demonstrated abolishing GSDMD-dependent pyroptosis by disulfiram attenuated CS-induced silicosis. Collectively, our data demonstrated that macrophage pyroptosis interacting with mitophagy contributes to pulmonary fibrosis via modulating mitochondria homeostasis, which may provide potential therapeutic targets.
Subject(s)
Pulmonary Fibrosis , Silicosis , Mice , Animals , Pulmonary Fibrosis/chemically induced , Silicon Dioxide/toxicity , Silicon Dioxide/metabolism , Mitophagy , Pyroptosis , Macrophages , Silicosis/drug therapy , Silicosis/metabolism , Silicosis/pathology , Protein Kinases/metabolism , Protein Kinases/pharmacology , Protein Kinases/therapeutic use , MitochondriaABSTRACT
BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Although most patients are initially sensitive to first-line combination chemotherapy with cisplatin and etoposide, chemotherapy drug resistance easily develops and quickly leads to tumour progression. Therefore, understanding the mechanisms of chemotherapy drug resistance and how to reverse it is key to improving the prognosis of patients with SCLC. Moreover, N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalysed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. METHODS: The effects of METTL3 on chemoresistance in SCLC cells were determined using qRT-PCR, Western blotting, immunohistochemistry, cell counting kit (CCK-8) assays, flow cytometry, and tumorigenicity experiments. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP qPCR, immunofluorescence, and drug inhibitor experiments were performed to confirm the molecular mechanism of Decapping Protein 2 (DCP2), which is involved in the chemoresistance of SCLC. RESULTS: In the present study, we found that METTL3 is a marker for poor SCLC prognosis, and it is highly expressed in chemoresistant SCLC cells. METTL3 promotes SCLC chemoresistance by positively regulating mitophagy. METTL3 induces m6A methylation of DCP2 and causes the degradation of DCP2, which promotes mitochondrial autophagy through the Pink1-Parkin pathway, leading to chemotherapy resistance. We also found that STM2457, a novel METTL3 inhibitor, can reverse SCLC chemoresistance. CONCLUSIONS: The m6A methyltransferase METTL3 regulates Pink1-Parkin pathway-mediated mitophagy and mitochondrial damage in SCLC cells by targeting DCP2, thereby promoting chemotherapy resistance in patients with SCLC.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , Drug Resistance, Neoplasm/genetics , Methyltransferases/genetics , Methyltransferases/metabolism , Mitophagy , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Protein Kinases/therapeutic useABSTRACT
Progress in ovarian cancer treatment lags behind other tumor types. With diagnosis usually at an advanced stage, there is a high demand for reliable prognostic biomarkers capable of the selection of effective chemo- and targeted therapies. Our goal was to establish a large-scale transcriptomic database and use it to uncover and rank survival-associated genes. Ovarian cancer cohorts with transcriptome-level gene expression data and clinical follow-up were identified from public repositories. All samples were normalized and entered into an integrated database. Cox univariate survival analysis was performed for all genes and was followed by multivariate analysis for selected genes involving clinical and pathological variables. False discovery rate was computed for multiple hypothesis testing and a 1% cutoff was used to determine statistical significance. The complete integrated database comprises 1816 samples from 17 datasets. Altogether, 2468 genes were correlated to progression-free survival (PFS), and 704 genes were correlated with overall survival (OS). The most significant genes were WBP1L, ASAP3, CNNM2, and NCAPH2 for progression-free survival and CSE1L, NUAK1, ALPK2, and SHKBP1 for overall survival. Genes significant for PFS were also preferentially significant for predicting OS as well. All data including HR and p values as well as the used cutoff values for all genes for both PFS and OS are provided to enable the ranking of future biomarker candidates across all genes. Our results help to prioritize genes and to neglect those which are most likely to fail in studies aiming to establish new clinically useful biomarkers and therapeutic targets in serous ovarian cancer.
Subject(s)
Cystadenocarcinoma, Serous , Ovarian Neoplasms , Humans , Female , Prognosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Ovarian Neoplasms/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/pathology , Transcription Factors , Protein Kinases/therapeutic use , Repressor Proteins/therapeutic useABSTRACT
Targeting the human epidermal growth factor receptor 2 (HER2) became a landmark in the treatment of HER2-driven breast cancer. Nonetheless, the clinical efficacy of anti-HER2 therapies can be short-lived and a significant proportion of patients ultimately develop metastatic disease and die. One striking consequence of oncogenic activation of HER2 in breast cancer cells is the constitutive activation of the extracellular-regulated protein kinase 5 (ERK5) through its hyperphosphorylation. In this study, we sought to decipher the significance of this unique molecular signature in promoting therapeutic resistance to anti-HER2 agents. We found that a small-molecule inhibitor of ERK5 suppressed the phosphorylation of the retinoblastoma protein (RB) in HER2 positive breast cancer cells. As a result, ERK5 inhibition enhanced the anti-proliferative activity of single-agent anti-HER2 therapy in resistant breast cancer cell lines by causing a G1 cell cycle arrest. Moreover, ERK5 knockdown restored the anti-tumor activity of the anti-HER2 agent lapatinib in human breast cancer xenografts. Taken together, these findings support the therapeutic potential of ERK5 inhibitors to improve the clinical benefit that patients receive from targeted HER2 therapies.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Protein Kinases/therapeutic use , Quinazolines/pharmacology , Cell CycleABSTRACT
Apoptosis of cardiomyocytes is a critical outcome of myocardial ischemia-reperfusion injury (MIRI), which leads to the permanent impairment of cardiac function. Upregulated E2F1 is implicated in inducing cardiomyocyte apoptosis, and thus intervention of the E2F1 signaling pathway via RNA interference may hold promising potential for rescuing the myocardium from MIRI. To aid efficient E2F1 siRNA (siE2F1) delivery into cardiomyocytes that are normally hard to transfect, a spherical, α-helical polypeptide (SPP) with potent membrane activity was developed via dendrimer-initiated ring-opening polymerization of N-carboxyanhydride followed by side-chain functionalization with guanidines. Due to its multivalent structure, SPP outperformed its linear counterpart (LPP) to feature potent siRNA binding affinity and membrane activity. Thus, SPP effectively delivered siE2F1 into cardiomyocytes and suppressed E2F1 expression both in vitro and in vivo after intramyocardial injection. The E2F1-miR421-Pink1 signaling pathway was disrupted, thereby leading to the reduction of MIRI-induced mitochondrial damage, apoptosis, and inflammation of cardiomyocytes and ultimately recovering the systolic function of the myocardium. This study provides an example of membrane-penetrating nucleic acid delivery materials, and it also provides a promising approach for the genetic manipulation of cardiomyocyte apoptosis for the treatment of MIRI.
Subject(s)
Dendrimers , Myocardial Reperfusion Injury , Rats , Animals , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/drug therapy , RNA, Small Interfering/pharmacology , Dendrimers/metabolism , Rats, Sprague-Dawley , Apoptosis , Peptides/genetics , Peptides/pharmacology , Peptides/metabolism , Guanidines/pharmacology , Guanidines/therapeutic use , Protein Kinases/metabolism , Protein Kinases/pharmacology , Protein Kinases/therapeutic use , E2F1 Transcription Factor/metabolism , E2F1 Transcription Factor/pharmacologyABSTRACT
Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients' daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient's daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.
Subject(s)
Anthelmintics , Antimalarials , Antineoplastic Agents , Breast Neoplasms , Diabetes Mellitus, Type 2 , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Metformin , Adenosine Monophosphate/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , Anthelmintics/therapeutic use , Anti-Bacterial Agents/therapeutic use , Antihypertensive Agents/therapeutic use , Antimalarials/therapeutic use , Antineoplastic Agents/therapeutic use , Atorvastatin/therapeutic use , Breast Neoplasms/pathology , Cholesterol , Diabetes Mellitus, Type 2/drug therapy , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Male , Mebendazole/therapeutic use , Metformin/therapeutic use , Mevalonic Acid/therapeutic use , Propranolol/therapeutic use , Protein Kinases/metabolism , Protein Kinases/therapeutic use , Proto-Oncogene Proteins B-raf , Receptors, Adrenergic, beta-2/therapeutic use , TyrosineABSTRACT
BACKGROUND: Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). This study aimed to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. METHODS: Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of various concentrations of glucose, pyruvate, or ATP-encapsulated liposomes. RESULTS: In this study, human CRC cell lines treated with irinotecan in high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in normal glucose concentrations. Irinotecan induced apoptosis and necroptosis, both mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it did not affect necroptosis. In contrast, pyruvate attenuated the receptor-interacting protein kinase 1/3-dependent necroptosis via free radical scavenging without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated the irinotecan-induced G0/G1 shift, whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere size while pyruvate prevented the deformation of spheroid mass. CONCLUSIONS: Glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to a quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, contributing to tumor recurrence. Our findings challenged the traditional view of ATP as the main factor for irinotecan chemoresistance and provided novel insights of pyruvate acting as an antioxidant responsible for drug insensitivity, which may shed light on the development of new therapies against recalcitrant cancers.
Subject(s)
Colorectal Neoplasms , Glucose , Adenosine Triphosphate/pharmacology , Adenosine Triphosphate/therapeutic use , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Apoptosis , Cell Line, Tumor , Cell Proliferation , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm , Free Radicals/pharmacology , Free Radicals/therapeutic use , Glucose/metabolism , Glucose/pharmacology , Glucose/therapeutic use , Humans , Irinotecan/pharmacology , Liposomes/pharmacology , Liposomes/therapeutic use , Mice , Neoplasm Recurrence, Local/drug therapy , Protein Kinases/pharmacology , Protein Kinases/therapeutic use , Pyruvic Acid/pharmacology , Pyruvic Acid/therapeutic use , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/therapeutic useABSTRACT
Intervertebral disk degeneration (IDD) is a common aging disease. Excessive apoptosis of nucleus pulposus (NP) cells has been widely considered a main contributor to IDD. Emerging science has shown that autophagy plays a protective role against apoptosis under oxidative stress. Vitamin D receptor (VDR) is a steroid hormone receptor that can regulate autophagy. The purpose of this study was to clarify whether VDR alleviates IDD by promoting autophagy. H2O2 stimulation was used to establish oxidative stress conditions. Initially, the expression level of VDR in human degenerative NP tissues was measured by immunohistochemistry. In addition, the CRISPR-dCas9-VPR system and siRNA were utilized to upregulate or downregulate VDR and Parkin expression, respectively. Autophagic and apoptotic markers were determined by Western blotting and RT-qPCR. Transmission electron microscopy was used to monitor the occurrence of autophagy in rat NP cells. VDR expression was downregulated in human degenerative NP tissues and H2O2-stimulated rat NP cells, indicating a negative correlation between VDR expression and IDD. VDR overexpression promoted mitophagy and prevented apoptosis and mitochondrial injury under oxidative stress. Additionally, mitophagy inhibition by 3-MA abolished the protective effect of VDR activation in vitro. Furthermore, VDR activation promoted mitophagy via the PINK1/Parkin pathway in H2O2-treated NP cells. This study demonstrates that VDR activation ameliorates oxidative damage and decreases NP cell apoptosis by promoting PINK1/Parkin-dependent mitophagy, indicating that VDR may serve as a promising therapeutic target in the management of IDD.
Subject(s)
Intervertebral Disc Degeneration , Nucleus Pulposus , Animals , Apoptosis , Humans , Hydrogen Peroxide/metabolism , Hydrogen Peroxide/pharmacology , Intervertebral Disc Degeneration/drug therapy , Intervertebral Disc Degeneration/genetics , Intervertebral Disc Degeneration/metabolism , Mitophagy , Nucleus Pulposus/metabolism , Oxidative Stress , Protein Kinases/metabolism , Protein Kinases/pharmacology , Protein Kinases/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Calcitriol/genetics , Receptors, Calcitriol/metabolism , Receptors, Calcitriol/therapeutic use , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/pharmacologyABSTRACT
Small-molecule kinase inhibitors have been well established and successfully developed in the last decades for cancer target therapies. However, intrinsic or acquired drug resistance is becoming the major barrier for their clinical application. With the development of immunotherapies, in particular the discovery of immune checkpoint inhibitors (ICIs), the combination of ICIs with other therapies have recently been extensively explored, among which combination of ICIs with kinase inhibitors achieves promising clinical outcome in a plethora of cancer types. Here we comprehensively summarize the potent roles of protein kinases in modulating immune checkpoints both in tumor and immune cells, and reshaping tumor immune microenvironments by evoking innate immune response and neoantigen generation or presentation. Moreover, the clinical trial and approval of combined administration of kinase inhibitors with ICIs are collected, highlighting the precise strategies to benefit cancer immune therapies.
Subject(s)
Neoplasms , Protein Kinases , Humans , Immune Checkpoint Inhibitors , Immunotherapy , Neoplasms/drug therapy , Neoplasms/pathology , Protein Kinases/therapeutic use , Tumor MicroenvironmentABSTRACT
BACKGROUND: Inflammation is the pathogenesis of various chronic diseases plaguing clinic for years.Fallopia multiflora (Thunb.) is a traditional Chinese herbal medicine with a long history of application in detoxification and anti-inflammation. 2,3,4',5-Tetrahydroxystilbene 2-o-D-glucoside (TSG) is a main active compound of F. multiflora. However, the mechanism of TSG in the treatment of inflammation remains unknown. METHODS: Network pharmacology and molecular docking were employed to explore the mechanism of anti-inflammatory effect of TSG. Potential targets of TSG and inflammation were obtained from Swiss Target Prediction, Pharm Mapper, and GeneCards database. Protein-protein interaction (PPI) networks, GO and KEGG pathway enrichment analysis were performed to elucidate the interaction of targets. Moreover, the anti-inflammatory effect of TSG was validated by in vitro experiments using flow cytometry, RT-qPCR, Western blot, and immunocytochemistry assays. RESULTS: PPI network and gene enrichment analysis showed that TSG may exert a protein kinase binding activity, and IKBKB, MAPK1, NFKBIA, and RELA were predicted as the targets of anti-inflammation. Verified by molecular docking and Western blot, TSG may target NF-κB and ERK2 related signals to alleviate inflammatory damage. Furthermore, TSG effectively downregulated the expression of inflammatory cytokine, the nuclear translocation of NF-κB p65, and the production of reactive oxygen species (ROS). CONCLUSION: TSG possesses significant anti-inflammatory effect. TSG may display a protein kinase binding activity and target NF-κB and ERK2 related signals to treat the inflammation. This work may enlighten the potential application of TSG in anti-inflammation and indicate network pharmacology was an effective tool for the further study of TCM.
Subject(s)
Drugs, Chinese Herbal , NF-kappa B , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Drugs, Chinese Herbal/pharmacology , Glucosides/pharmacology , Glucosides/therapeutic use , Humans , Inflammation/drug therapy , Molecular Docking Simulation , NF-kappa B/metabolism , Network Pharmacology , Protein Kinases/therapeutic useABSTRACT
INTRODUCTION: Chronic myeloid leukemia (CML) is a malignant hemopathy within the framework of chronic myeloproliferative syndromes, predominant on the granular line. Her drug treatment is based on tyrosine kinase inhibitors (TKIs) which inhibit the abnormal BCR-ABL protein kinase that causes CML and thus block the signals that cause cancer cells to multiply abnormally. However, other proteins are also inhibited, so they can cause a wide range of adverse effects (AEs). The objective of this study was to study the prevalence of AEs of TKIs used in the therapeutic management of CML by the hematology department of University Hospital Center (UHC) of Sidi Bel-Abbes in Algeria and that of the ITK discontinuation following an AE. MATERIALS AND METHODS: It was a retrospective descriptive study carried out over a period of four months, from April 01st, 2021 to July 31st, 2021, on CML patients treated with TKI in the hematology department of Sidi Bel-Abbes HUC in Algeria. The primary outcome measure was the prevalence of AEs associated with the use of normal dosages or overdose of the following TKIs: Imatinib, Dasatinib and Nilotinib. Data were collected from patient charts, filled by doctors of hematology department, using questionnaire, and analyzed by Statistical Package for the Social Sciences software, version 20. RESULTS: A total of 40 patients were included, including 22 women, mean age 51.55±11.66years (23-78). Twenty-six patients reported at least one AE. Among the 106 AEs declared, 69 AEs (65.09 %) declared with Imatinib, 26 AEs (24.53 %) with Dasatinib and 11 AEs (10.38 %) with Nilotinib. A predominance of musculoskeletal effects 43 (40.56 %), followed by general disorders 18 (17 %), myelosuppression 14 (13.20 %) and digestive system 12 (11.32 %). AEs were responsible for permanent discontinuation of ITK in three cases (11.54 %), including two cases (07.70 %) on Imatinib because of neutropenia and one case (03.84 %) onDasatinibsuffering from pleural effusion. AEs could be controlled in 13 (50 %) of cases, including 9 (34.62%) by temporary discontinuation and 4 (15.38 %) by reducing the dosage, allowing improvement of symptoms and continuation or reintroduction of treatment. CONCLUSION: The prevalence of AEs was high in the studied population, their occurrence was inevitable, good management of AEs from the start of treatment is necessary to avoid switching to another TKI, especially in good responders. It is recommended to establish a low-sodium diet beforehand for all TKIs and a low-carbohydrate diet, especially for Nilotinib, and not to rush to stop the TKI because most often, EIs regress over time in order to allow good therapeutic adherence and obtain better results.
Subject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Adult , Female , Humans , Middle Aged , Antineoplastic Agents/adverse effects , Dasatinib/adverse effects , Hospitals, University , Iatrogenic Disease , Imatinib Mesylate/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Prevalence , Protein Kinase Inhibitors/adverse effects , Protein Kinases/therapeutic use , Retrospective StudiesABSTRACT
Glioma is the most common primary malignant brain tumors in adults. Despite considerable advances in treatment, the clinical outcome remains dismal. Translocator protein 18 kDa (TSPO), an evolutionarily conserved transmembrane protein, has always been found to be elevated in glioma, which predicts a poor prognosis. However, studies on the regulatory network of TSPO in glioma are limited. The Cancer Genome Atlas (TCGA) and our research group cohorts demonstrated that TSPO expression was also highly expressed in glioma tissues and glioma cell lines. Inhibition of TSPO expression significantly reduced glioma cell proliferation and mobility in vitro. Suppression of TSPO decreased the expression of MAPK-activated protein kinase 3 (MAPKAPK3) and increased the degradation rate of its mRNA. TSPO directly interacts with ELAV1-like RNA-binding protein 1 (HUR) and promotes the nuclear-cytoplasmic shuttling of HUR. Inhibition of HUR decreased MAPKAPK3 expression and cell proliferation and mobility, whereas overexpression of MAPKAPK3 reversed the effects. Overexpression of HUR in TSPO-knockdown cells enhanced the mRNA stability of MAPKAPK3. Furthermore, rescue experiments show that the HUR/MAPKAPK3 axis accounts for the TSPO-mediated effects on glioma cell proliferation and mobility. Together, our present study indicated that TSPO may promote the nuclear-cytoplasmic shuttling of HUR, thus increasing the mRNA stability of MAPKAPK3 and promoting the proliferation and mobility of glioma cells. The HUR/MAPKAPK3 axis may be key targets for blocking the effects of TSPO and may contribute to glioma therapy.
Subject(s)
ELAV-Like Protein 1 , Glioma , Adult , Cell Line, Tumor , ELAV-Like Protein 1/genetics , ELAV-Like Protein 1/metabolism , Gene Expression Regulation, Neoplastic , Glioma/metabolism , Humans , Protein Kinases/genetics , Protein Kinases/metabolism , Protein Kinases/therapeutic use , RNA-Binding Proteins/metabolism , Receptors, GABA/genetics , Receptors, GABA/metabolism , Receptors, GABA/therapeutic useABSTRACT
BACKGROUND: Cancer is the world's third deadliest disease. Despite the availability of numerous treatments, researchers are focusing on the development of new drugs with no resistance and toxicity issues. Many newly synthesized drugs fail to reach clinical trials due to poor pharmacokinetic properties. Therefore, there is an imperative requisite to expand novel anticancer agents with in vivo efficacy. OBJECTIVE: This review emphasizes synthetic methods, contemporary strategies used for the inclusion of oxazole moiety, mechanistic targets, along with comprehensive structure-activity relationship studies to provide perspective into the rational design of highly efficient oxazole-based anticancer drugs. METHODS: Literature related to oxazole derivatives engaged in cancer research is reviewed. This article gives a detailed account of synthetic strategies, targets of oxazole in cancer, including STAT3, Microtubules, G-quadruplex, DNA topoisomerases, DNA damage, protein kinases, miscellaneous targets, in vitro studies, and some SAR studies. RESULTS: Oxazole derivatives possess potent anticancer activity by inhibiting novel targets such as STAT3 and Gquadruplex. Oxazoles also inhibit tubulin protein to induce apoptosis in cancer cells. Some other targets such as DNA topoisomerase enzyme, protein kinases, and miscellaneous targets including Cdc25, mitochondrial enzymes, HDAC, LSD1, HPV E2 TAD, NQO1, Aromatase, BCl-6, Estrogen receptor, GRP-78, and Keap-Nrf2 pathway are inhibited by oxazole derivatives. Many derivatives showed excellent potencies on various cancer cell lines with IC50 values in nanomolar concentrations. CONCLUSION: Oxazole is a five-membered heterocycle, with oxygen and nitrogen at 1 and 3 positions, respectively. It is often combined with other pharmacophores in the expansion of novel anticancer drugs. In summary, oxazole is a promising entity to develop new anticancer drugs.
Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Neoplasms/drug therapy , Oxazoles/pharmacology , Oxazoles/therapeutic use , Protein Kinases/therapeutic use , Structure-Activity RelationshipABSTRACT
A DOENÇA: O câncer de mama triplo negativo (CMTN) é definido pela ausência da expressão dos receptores de estrogênio (RE), receptores de progesterona (RP) e receptores do fator de crescimento epidermal humano (HER2 human epidermal growth factor receptor 2), que são marcadores presentes na maioria dos tipos de câncer de mama e utilizados para a definição do tratamento. Em média, entre os casos de câncer de mama, 15 a 20% são definidos como CMTN e mais de 30% desses casos progridem para doença metastática. Diferente dos outros tipos de câncer de mama, sua frequência é maior entre mulheres jovens abaixo de 50 anos, com maior prevalência entre aquelas com 35 anos. Os pacientes com CMTN apresentam geralmente tumores em graus mais avançados e desfechos clínicos ruins em termos de sobrevida global e sobrevida livre de doença. As curvas de sobrevida no CMTN, diferentes de outros subtipos de câncer de mama, são caracterizadas por um aumento na recidiva e uma diminuição na sobrevida durante os primeiros três a cinco anos após o diagnóstico. Apesar de avanços substanciais nos resultados clínicos de novos tratamentos para o câncer de mama nos últimos anos, o subtipo de CMTN permanece uma área com necessidade clínica ainda não atendida. Como não apresentam expressão de RE, RP e HER2, os tratamentos com hormonioterapia e terapia anti-HER2 não estão indicados para esses pacientes, sendo adotada a estratégia de quimioterapia, além da cirurgia e radioterapia, conforme preconizado nas Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama. TRATAMENTO DISPONÍVEL: As Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama de 2019 não fazem recomendação específica para o tratamento dos pacientes com CMTN. Entretanto, entre os medicamentos utilizados para o tratamento dos tipos de câncer de mama é relatado que a associação do bevacizumabe ao paclitaxel nos pacientes com CMTN proporciona um aumento na taxa de resposta e na sobrevida livre de progressão de doença sem alterar a sobrevida mediana global. De acordo com as Diretrizes de Tratamentos Oncológicos recomendados pela Sociedade Brasileira de Oncologia Clínica (SBOC) de 2021 para o câncer de mama metastático, os pacientes com CMTN devem ser tratados com quimioterapia. O regime deve ser individualizado com base no tamanho, localização e características do tumor; e sintomas e preferências do paciente. Além disso, devem ser considerados a resposta e o intervalo sem progressão com os tratamentos anteriores. Os taxanos e antracíclicos são os medicamentos do tratamento padrão tanto em (neo) adjuvância como na primeira linha de doença metastática. A doxorrubicina e a epirrubicina são os antracíclicos mais comumente usados no tratamento do câncer de mama. A escolha entre os taxanos é determinada pelo tratamento prévio, podendo-se escolher entre o paclitaxel e o docetaxel, de acordo com o perfil de toxicidade e preferência do paciente. No caso de pacientes refratários a antracíclicos e taxanos, existe uma série de opções de tratamentos quimioterápicos, que podem ser utilizados em monoterapia e associados. Os principais medicamentos utilizados em monoterapia são: capecitabina, eribulina, vinorelbine e gemcitabina. As terapias com medicamentos associados mais comumente utilizados são paclitaxel com gencitabina, docetaxel com capecitabina e combinações com platinas6 . Além desses, a adição de bevacizumabe à quimioterapia, em primeira ou segunda linha, resultou em aumento modesto de resposta objetiva e sobrevida livre de progressão, sem aumento de sobrevida global. ESTRATÉGIA DE BUSCA: Os medicamentos em fase de pesquisa clínica para câncer de mama triplo negativo foram identificados, inicialmente, na base de pesquisa clínica Clinicatrials.gov em 19 de abril de 2021, com filtros para estudo de intervenção, em fase 3 de ensaio clínico e em andamento. Foram excluídos da análise os estudos cuja situação estava desatualizada a mais de um ano na base e os estudos cujo objetivo da tecnologia era atuar como adjuvante ou neoadjuvante. Além disso, foram consultados as bases eletrônicas MEDLINE (via PubMed) e EMBASE (via Periódicos Capes) em 19 de abril de 2021; e Cortellis15, da Clarivate Analytics, em 28 de abril de 2021, utilizando o termo "advanced triple negative breast cancer" e seus sinônimos, com filtro para tecnologias em desenvolvimento na fase 3 de ensaio clínico. TECNOLOGIAS EM DESENVOLVIMENTO: Foram identificados 55 ensaios clínicos de fase 3, com 10 tecnologias em desenvolvimento para a indicação estudada e que foram elegíveis para compor este informe20: sacituzumabe govitecan, olaparibe, carelizumabe, pembrolizumabe, toripalimabe, TQB2450, alpelisibe, capivasertibe, ipatasertibe, e bicalutamida. O quadro 1 apresenta essas tecnologias consideradas com informações sobre sua classe terapêutica e situação regulatória nas agências sanitárias FDA, EMA, Health Canada e Anvisa. Algumas tecnologias estão em estágios iniciais do ensaio clínico de fase 3 sem resultados parciais publicados, entretanto, suas características serão descritas nesta seção. São eles: carelizumabe, toripalimabe, TQB2450, alpelisibe, capivasertibe e bicalutamida. CONSIDERAÇÕES FINAIS: O câncer de mama triplo negativo localmente avançado irressecável ou metastático é uma doença heterogênea com um prognóstico ruim e atualmente com poucas opções de tratamento em uso. A aprovação do medicamento atezolizumabe no Brasil, para uso em combinação com nab-paclitaxel trouxe um avanço para o tratamento alvo-direcionado para essa população. Este informe apresentou o panorama das tecnologias mais promissoras em fase de desenvolvimento clínico para a doença. Algumas em vias de administração com maior comodidade posológica, como a via oral (olaparibe, alpelisibe, capivasertibe, ipatasertibe e bicalutamida). A identificação dessas tecnologias neste informe projeta uma expectativa sobre diferentes vias moleculares de combate a doença que podem impactar no prognóstico dos pacientes com câncer de mama triplo negativo localmente avançado irressecável ou metastático. Algumas dessas tecnologias estão em fases finais de pesquisa clínica com resultados publicados e já são autorizadas ou iniciaram seus pedidos nas agências sanitárias internacionais. Entre elas destacam-se o sacituzumabe govitecan e o pembrolizumabe, ambas com autorização de comercialização recente pela agência sanitária dos EUA para a indicação de CMTN. Mesmo sendo essa autorização em um contexto de aprovação acelerada, que necessita de acompanhamento dos resultados dos estudos em andamento, existe um avanço para o tratamento da doença que hoje ainda é considerada com uma necessidade não atendida. O sacituzumabe govitecan obteve bons resultados para os desfechos de sobrevida livre de progressão, sobrevida global e taxa de resposta objetiva. Os resultados com pembrolizumabe, apesar de não indicarem uma diferença grande em relação ao comparador nos desfechos de sobrevida livre de progressão, se mostraram consistentes ao longo do tempo e foram maiores conforme o aumento da expressão de PD-1, indicando que pode existir uma relação direta com esse marcador. As tecnologias em desenvolvimento identificadas estão direcionadas a alvos moleculares específicos do desenvolvimento da doença, de modo que a definição dos subtipos moleculares é essencial para o planejamento das estratégias de tratamento, que cada vez mais serão baseadas em medicina personalizada, como por exemplo, a quantificação da expressão do PD-1 como biomarcador preditivo de benefício para a escolha dos pacientes que devem fazer imunoterapia. Espera-se que a conclusão dos estudos em andamento possa trazer resultados clínicos robustos que possam aumentar as opções terapêuticas do tratamento e assim representar um melhor prognóstico da doença.
Subject(s)
Humans , Protein Kinases/therapeutic use , Immunoglobulin G/therapeutic use , Immunoconjugates/therapeutic use , Phosphatidylinositol 3-Kinases/therapeutic use , Androgen Receptor Antagonists/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/secondary , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Brazil , Efficacy , Cost-Benefit Analysis , Technological Development and Innovation ProjectsABSTRACT
Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.
Subject(s)
Immunotherapy/methods , Neoplasms/therapy , Clinical Trials as Topic , Combined Modality Therapy , Humans , Immunotherapy/trends , Immunotherapy, Adoptive , Neoplasms/immunology , Protein Kinases/pharmacology , Protein Kinases/therapeutic useABSTRACT
Recent ï¬ndings have shown that dysregulation of circular RNAs (circRNAs) is implicated in various cancers. However, the contribution of circRNAs in oral squamous cell carcinoma (OSCC) remains largely unexplored. We screened circRNA expression profiles using a circRNA microarray in paired OSCC and normal tissues and explored the clinical significance of a downregulated circRNA, circ-PKD2. Moreover, the biological function of circ-PKD2 in OSCC was investigated both in vitro and in vivo. We found that downregulation of circ-PKD2 in OSCC correlated signiï¬cantly with aggressive characteristics. Further analysis revealed that overexpression of circ-PKD2 inhibited OSCC cell proliferation, migration and invasion, induced apoptosis and cell cycle arrest, which were promoted by knockdown of circ-PKD2. In addition, circ-PKD2 was identified as a sponge for miR-204-3p and upregulated the expression of adenomatous polyposis coli 2 (APC2), which was the functional target of miR-204-3p. Moreover, circ-PKD2 attenuated the oncogenic effects of miR-204-3p-mediated APC2 on OSCC progression via multiple signaling pathways. These results demonstrate that the circ-PKD2/miR-204-3p/APC2 axis represents a novel pathway involved in the pathogenesis of OSCC and may serve as a novel therapeutic target of OSCC.
Subject(s)
Carcinoma, Squamous Cell/genetics , Cytoskeletal Proteins/genetics , MicroRNAs/genetics , Mouth Neoplasms/genetics , Protein Kinases/genetics , Animals , Apoptosis/genetics , Carcinogenesis/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Cell Line, Tumor , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Heterografts , Humans , Male , Mice , Microarray Analysis , Mouth Neoplasms/therapy , Protein Kinase D2 , Protein Kinases/therapeutic use , RNA, Circular/genetics , RNA, Circular/therapeutic use , Signal TransductionABSTRACT
A growing understanding of the immune system and its anti-tumor functions has been imperative for the comprehension of malignant processes and beneficial in the pursuit of effective cancer treatments. To defend the body, immune cells must be able to differentiate between self and foreign cells using checkpoints, allowing the immune cells to attack foreign cells. Among the different types of immune target therapies recently developed, checkpoint inhibitors have come to the forefront in cancer treatment, encouraging their study in numerous different types of cancer, including hepato-pancreato-biliary malignancies (HPB). Traditionally, these malignancies have been treated with standard cytotoxic chemotherapy, but with little benefit in the metastatic setting. However, impressive results with checkpoint inhibitor therapy have been noted in a number of cancers as these agents enable immune cells to kill cancer cells more efficiently. Two classes of checkpoint inhibitors being extensively studied are inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ligand and programmed cell death protein 1 and its ligand (PD-1 and PD-L1). Checkpoint inhibitors have an advantage over other types of immunotherapies, such as cell-based therapies, in that they are commercially available and can be given to patients with a range of pathologies and regardless of HLA status. Herein, we will discuss the application of immune checkpoint inhibitors to HPB malignancies as well as the limitations of these medications in these cancers.