Deregulation of protein kinases is often associated with uncontrolled cell proliferation in various tumours and the inhibition of kinase activity remains an important target for anti-tumour drug development. Here, we report a novel series of 2-aminocyclohexylamino-6-(substituted benzylamino/anilino)-9-cyclopentylpurine derivatives conjugated with putrescine, spermidine or spermine moiety in an effort to expand library of highly potent 2,6,9-trisubstituted purine kinase inhibitors. Presented aniline-type conjugates exhibit significant cytotoxic activity in MV4-11 and EOL-1 cell lines which correlates with FLT3-ITD and PDGFRα inhibition. Furthermore, 6-anilinopurines affected MAPK and STAT pathways in the treated MV4-11 cells and induced cell cycle arrest in the G1 phase. 6-Benzylaminopurines showed comparable CDK2 inhibitory activity to 6-anilinopurines, however, the PDGFRα and FLT3-ITD inhibition was strongly suppressed. Our results show that novel compounds containing aniline in the structure can be involved in the development of potent tyrosine kinase inhibitors with strong activity toward acute myeloid leukemia or chronic eosinophilic leukemia.

• MeSH
• Protein Kinase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Protein Kinases metabolism   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Purines chemical synthesis   chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Fluorescein is a fluorescent dye used as a diagnostic tool in various fields of medicine. Although fluorescein itself possesses low toxicity, after photoactivation, it releases potentially toxic molecules, such as singlet oxygen (1O2) and, as we demonstrate in this work, also carbon monoxide (CO). As both of these molecules can affect physiological processes, the main aim of this study was to explore the potential biological impacts of fluorescein photochemistry. In our in vitro study in a human hepatoblastoma HepG2 cell line, we explored the possible effects on cell viability, cellular energy metabolism, and the cell cycle. We observed markedly lowered cell viability (≈30%, 75-2400 μM) upon irradiation of intracellular fluorescein and proved that this decrease in viability was dependent on the cellular oxygen concentration. We also detected a significantly decreased concentration of Krebs cycle metabolites (lactate and citrate < 30%; 2-hydroxyglutarate and 2-oxoglutarate < 10%) as well as cell cycle arrest (decrease in the G2 phase of 18%). These observations suggest that this photochemical reaction could have important biological consequences and may account for some adverse reactions observed in fluorescein-treated patients. Additionally, the biological activities of both 1O2 and CO might have considerable therapeutic potential, particularly in the treatment of cancer.

• MeSH
• Angiography MeSH
• Hep G2 Cells MeSH
• Citric Acid Cycle drug effects   radiation effects   MeSH
• Fluorescein chemistry   pharmacology   MeSH
• Photochemical Processes MeSH
• Cell Cycle Checkpoints drug effects   radiation effects   MeSH
• Humans MeSH
• Carbon Monoxide analysis   MeSH
• Gas Chromatography-Mass Spectrometry MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Singlet Oxygen analysis   MeSH
• Light MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.

• MeSH
• Apoptosis drug effects   genetics   MeSH
• Cisplatin pharmacology   MeSH
• Doxorubicin pharmacology   MeSH
• Fluorouracil pharmacology   MeSH
• HCT116 Cells MeSH
• Colorectal Neoplasms drug therapy   genetics   metabolism   pathology   MeSH
• Cell Cycle Checkpoints drug effects   genetics   MeSH
• Humans MeSH
• Mice, Nude MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 agonists   genetics   metabolism   MeSH
• Drug Discovery MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   pharmacology   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   MeSH
• Pyrroles chemical synthesis   pharmacology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Drug Synergism MeSH
• Thiazoles chemical synthesis   pharmacology   MeSH
• Protein Binding MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of β-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.

• MeSH
• Antimalarials chemical synthesis   chemistry   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• A549 Cells MeSH
• Quinolines chemical synthesis   chemistry   pharmacology   MeSH
• Hydrazines chemical synthesis   chemistry   pharmacology   MeSH
• Inhibitory Concentration 50 MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Acetic Acid chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Malaria drug therapy   MeSH
• MCF-7 Cells MeSH
• Disease Models, Animal MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Thiazoles chemical synthesis   chemistry   pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Východiska: Léčebné možnosti pokročilého karcinomu jícnu jsou dlouhodobě považovány za značně omezené. V posledních letech proběhla řada klinických studií, jež u této diagnózy hodnotily efekt checkpoint inhibitorů, z nichž vyplynulo, že pacienti s vyšší expresí PD-L1 mohou profitovat z terapie pembrolizumabem, a to zejména v případě spinocelulárního histologického subtypu. Případ: V naší kazuistice budeme demonstrovat podání pembrolizumabu v 1. linii terapie u generalizovaného spinocelulárního karcinomu jícnu s expresí PD-L1 > 70 %. Imunoterapií bylo docíleno kompletní remise onemocnění. Závěr: Naše kazuistika ukazuje důležitost vyšetřování exprese PD-L1 u pokročilého karcinomu jícnu. Podle dosavadních zjištění se zdá, že imunoterapie má na rozdíl od chemoterapie potenciál vyvolat dlouhodobou léčebnou odpověď.

Background: The treatment options in advanced stage of esophageal cancer are very limited. In recent years, a number of clinical trials have evaluated the effect of checkpoint inhibitors in this diagnosis. Case: In our case report, we will demonstrate the administration of pembrolizumab in first-line therapy in generalized squamous cell carcinoma of the esophagus with PD-L1 expression > 70%. Complete remission of the disease was achieved by this approach. Conclusion: Our case report shows the importance of investigating the expression of PD-L1 in advanced esophageal cancer. According to previous findings, immunotherapy, unlike chemotherapy, appears to have the potential to elicit a long-term response.

• Keywords
• pembrolizumab,
• MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   MeSH
• Immunotherapy methods   MeSH
• Immune Checkpoint Inhibitors analysis   MeSH
• Clinical Studies as Topic MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Esophageal Neoplasms * diagnosis   drug therapy   immunology   MeSH
• Antineoplastic Agents, Immunological therapeutic use   MeSH
• Antineoplastic Protocols MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Pharmacological inhibition of cyclin-dependent kinases has emerged as a possible treatment option for various cancer types. We recently identified substituted imidazo[1,2-c]pyrimidin-5(6H)-ones as inhibitors of cyclin-dependent kinase 2 (CDK2). Here, we report the synthesis of derivatives modified at positions 2, 3, 6 or 8 prepared using Suzuki-Miyaura cross-coupling, halogenation, Dimroth-type rearrangement and alkylation as the main synthetic methods. The compounds displayed micro- to submicromolar inhibition of CDK2/cyclin E activity. Binding of the most potent compound 3b to CDK2 was determined using isothermal titration calorimetry. The co-crystal structure of 3b in complex with fully active CDK2 was solved, revealing the binding mode of 3b in the ATP pocket and a hydrogen bonding interaction with hinge region residue Leu83. Evaluation against leukaemia cell lines revealed low cytotoxicity, which is in line with the high selectivity towards CDK2. This study demonstrates that substituted imidazo[1,2-c]pyrimidines can be exploited for future kinase inhibitor development.

• MeSH
• Cyclin-Dependent Kinase 2 antagonists & inhibitors   metabolism   MeSH
• Imidazoles chemistry   metabolism   pharmacology   MeSH
• Protein Kinase Inhibitors chemical synthesis   metabolism   pharmacology   MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   metabolism   pharmacology   MeSH
• Pyrimidines chemistry   metabolism   pharmacology   MeSH
• Molecular Dynamics Simulation MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Hydrogen Bonding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND/AIM: Multiple myeloma is a highly heterogeneous disease of clonal plasma cells. Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their precise mechanisms of actions are not well understood. MATERIALS AND METHODS: Cell-cycle regulation and pro-apoptotic effects of two histone deacetylase inhibitors, suberohydroxamic acid (SAHA) and suberoylanilide hydroxamic acid (SBHA), were analyzed in multiple myeloma cell lines RPMI8226 and U266 with differing TP53 status using gene-expression analysis. RESULTS: Enhanced expression of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21WAF/CIP1) detected in the TP53-deleted U266 cell line after SAHA treatment indicates the P53-independent mode of transcriptional activation of CDKN1A gene. In contrast, CDKN1A gene expression was significantly increased by both SBHA and SAHA treatment of TP53-mutated RPMI8226 cells. CONCLUSION: SAHA appears to be a potentially effective pro-apoptotic and anticancer drug with universal application in the treatment of heterogeneous populations of multiple myeloma cells.

• MeSH
• Apoptosis drug effects   MeSH
• Cyclin-Dependent Kinase Inhibitor p21 antagonists & inhibitors   genetics   MeSH
• Histone Deacetylase Inhibitors pharmacology   MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Hydroxamic Acids pharmacology   MeSH
• Humans MeSH
• Multiple Myeloma drug therapy   genetics   metabolism   pathology   MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Východiská: Používanie inhibítorov imunitných kontrolných bodov (imunitných checkpoint inhibítorov – ICI) dramaticky zlepšilo prognózu mnohých onkologických pacientov. Ich narastajúce používanie však odhalilo aj viacero neočakávaných nežiaducich účinkov – medzi nimi aj kardiovaskulárnych komplikácií. Zvýšená pozornosť sa im začala venovať až v ostatných rokoch, a to najmä pre ich potenciálne fatálny charakter. Ku kardiotoxicite tejto liečby patria myokarditída, poruchy rytmu (atrioventrikulárne blokády, predsieňové a komorové arytmie), perikarditída, infarkt myokardu, dysfunkcia ľavej komory/zlyhávanie srdca, dilatačná kardiomyopatia, kardiogénny šok a náhla kardiálna smrť. Riziko kardiotoxicity ICI sa môže okrem duálnej ICI terapie zvyšovať aj v kombinácii s inou potenciálne kardiotoxickou protinádorovou liečbou, s preexistujúcim poškodením srdca, diabetom, autoimunitným ochorením a niektorými ďalšími rizikovými faktormi. V súčasnosti neexistujú odporúčania pre predikciu a manažment kardiotoxicity asociovanej s ICI. Cieľ: V predkladanom článku stručne sumarizujeme poznatky týkajúce sa kardiotoxicity indukovanej týmito inhibítormi a uvádzame novú definíciu myokarditídy navodenej protinádorovou liečbou spolu s návrhom manažmentu imunitou navodenej myokarditídy vypracovaným expertmi v oblasti kardioonkológie.

Background: The use of immune checkpoint inhibitors has dramatically improved the prognosis of many cancer patients. However, their increasing use has also revealed several unexpected side effects – including cardiovascular complications. Increased attention was paid to them in recent years only, especially due to their potentially fatal character. Checkpoint inhibitors cardiotoxicity includes myocarditis, rhythm disorders (atrioventricular blocks, atrial and ventricular arrhythmias), pericarditis, myocardial infarction, left ventricular dysfunction/heart failure, dilated cardiomyopathy, cardiogenic shock and sudden cardiac death. The risk of ICI-associated cardiotoxicity is increased in patients treated with dual immune therapy, in combination with other cardiotoxic drugs, with preexisting cardiac damage, diabetes mellitus, underlying autoimmune disease and some other factors. Currently, there are no guidelines for prediction and management of ICI-associated cardiotoxicity. Purpose: Herein, we briefly summarize the findings regarding checkpoint inhibitor-induced cardiotoxicity and provide a new definition of anti-tumor-induced myocarditis together with a suitable design for immune- induced myocarditis management prepared by experts from the field of cardiooncology.

• MeSH
• Immunotherapy adverse effects   MeSH
• Cardiotoxicity MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• Myocarditis etiology   MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Antineoplastic Agents, Immunological * adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• Survival Analysis MeSH
• Gastrointestinal Neoplasms drug therapy   pathology   MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Congresses as Topic MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• Esophageal Neoplasms drug therapy   pathology   MeSH
• Prostatic Neoplasms, Castration-Resistant drug therapy   MeSH
• Breast Neoplasms drug therapy   pathology   MeSH
• Carcinoma, Non-Small-Cell Lung drug therapy   MeSH
• Nivolumab therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Newspaper Article MeSH
• Randomized Controlled Trial MeSH

Sulfur mustard [bis(2-chloroethyl) sulfide; SM] is a highly poisonous chemical warfare agent. The mechanism of its cytotoxicity affects several pathways, which cause cell damage or death. The main organ affected in case of exposure to both aerosol and vapor is lungs. The present study focuses on time- and concentration-dependent changes in human lung fibroblasts NHLF and lung epithelial cell line A-549. The cells were treated with SM at the concentrations of 5, 10 and 100 µM and signs of stress response were evaluated during 1-72 h post-treatment. Parameters for testing included cell viability and morphology, loss of transmembrane mitochondrial potential, apoptosis, oxidative stress, changes in the cell cycle, and ATM kinase activation. The cytotoxic effect of SM resulted in a time-dependent decrease in viability of A-459 associated with apoptosis more markedly than in NHLF. We did not observe any generation of reactive oxygen species by SM. SM at concentrations of 5 and 10 µM induced the S-phase cell cycle arrest at both cell lines. On the other hand, 100 µM caused nonspecific cell cycle arrest. ATM kinase was activated transiently. The results indicate that NHLF cells are less prone to toxic damage by SM in case of cell viability, apoptosis and loss of transmembrane mitochondrial potential. The analysis provides a time-related cytotoxic profile of A-549 and NHLF cells for further investigation into the prevention of SM toxic effects and their potential treatment.

• MeSH
• Apoptosis drug effects   MeSH
• A549 Cells MeSH
• Time Factors MeSH
• Chemical Warfare Agents toxicity   MeSH
• Epithelial Cells drug effects   MeSH
• Fibroblasts drug effects   MeSH
• Stress, Physiological drug effects   MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Lung cytology   MeSH
• Reactive Oxygen Species MeSH
• Cell Survival drug effects   MeSH
• Mustard Gas toxicity   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH