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1.
Int J Mol Sci ; 25(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892180

RESUMO

The incidence of thyroid cancer, one of the most common forms of endocrine cancer, is increasing rapidly worldwide in developed and developing countries. Various risk factors can increase susceptibility to thyroid cancer, but particular emphasis is put on the role of DNA repair genes, which have a significant impact on genome stability. Polymorphisms of these genes can increase the risk of developing thyroid cancer by affecting their function. In this article, we present a concise review on the most common polymorphisms of selected DNA repair genes that may influence the risk of thyroid cancer. We point out significant differences in the frequency of these polymorphisms between various populations and their potential relationship with susceptibility to the disease. A more complete understanding of these differences may lead to the development of effective prevention strategies and targeted therapies for thyroid cancer. Simultaneously, there is a need for further research on the role of polymorphisms of previously uninvestigated DNA repair genes in the context of thyroid cancer, which may contribute to filling the knowledge gaps on this subject.


Assuntos
Reparo do DNA , Predisposição Genética para Doença , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/genética , Reparo do DNA/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único
2.
Int J Mol Sci ; 24(10)2023 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-37239848

RESUMO

The current study continues the evaluation of the anticancer potential of three de novo synthesized pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides-MM129, MM130, and MM131-against human cancer cells of HeLa, HCT 116, PC-3, and BxPC-3 lines. The pro-apoptotic activity of the investigated sulfonamides was shown by observations of changes in the mitochondrial transmembrane potential of the tested cells, externalization of phosphatidylserine on the cellular membrane surface, and cell morphology in microscopic imaging. The computational studies have shown that MM129 exhibited the lowest binding energy values when docked against CDK enzymes. In addition, the highest stability was shown for complexes formed between MM129 and CDK5/8 enzymes. All examined compounds induced cell cycle arrest in the G0/G1 phase in the BxPC-3 and PC-3 cells and simultaneously caused the accumulation of cells in the S phase in the HCT 116 cells. In addition, the increase in the subG1 fraction was observed in PC-3 and HeLa cells. The application of a fluorescent H2DCFDA probe revealed the high pro-oxidative properties of the tested triazine derivatives, especially MM131. In conclusion, the obtained results suggest that MM129, MM130, and MM131 exhibited strong pro-apoptotic properties towards investigated cells, mainly against the HeLa and HCT 116 cell lines, and high pro-oxidative potential as well. Moreover, it is suggested that the anticancer activity of the tested compounds may be associated with their ability to inhibit CDK enzymes activities.


Assuntos
Antineoplásicos , Sulfonamidas , Humanos , Estrutura Molecular , Células HeLa , Sulfonamidas/farmacologia , Sulfonamidas/química , Triazinas/farmacologia , Triazinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular , Estresse Oxidativo , Sulfanilamida/farmacologia , Apoptose , Proliferação de Células
3.
Int J Mol Sci ; 24(4)2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36835469

RESUMO

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides constitute a novel group of heterocyclic compounds with broad biological activities including anticancer properties. The compounds investigated in this study (MM134, -6, -7, and 9) were found to have antiproliferative activity against BxPC-3 and PC-3 cancer cell lines in micromolar concentrations (IC50 0.11-0.33 µM). Here, we studied the genotoxic potential of the tested compounds with alkaline and neutral comet assays, accompanied by immunocytochemical detection of phosphorylated γH2AX. We found that pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides induce significant levels of DNA damage in BxPC-3 and PC-3 cells without causing genotoxic effects in normal human lung fibroblasts (WI-38) when used in their respective IC50 concentrations (except for MM134) and showed a dose-dependent increase in DNA damage following 24 h incubation of tested cancer cells with these agents. Furthermore, the influence of MM compounds on DNA damage response (DDR) factors was assessed using molecular docking and molecular dynamics simulation.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Triazinas/química , Dano ao DNA , Ensaio Cometa , Antineoplásicos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Proliferação de Células
4.
Int J Mol Sci ; 24(13)2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37446136

RESUMO

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides (MM-compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM-compounds (MM134, -6, -7, and -9). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling. The compounds' cytotoxic and pro-oxidative properties were also assessed. Additionally, computational studies were performed to demonstrate the potential of the scaffold for future drug discovery endeavors. MM-compounds exhibited strong micromolar (0.06-0.35 µM) anti-proliferative and pro-oxidative activity in two cancer cell lines (BxPC-3 and PC-3). Activation of caspase 3/7 was observed following a 24-h treatment of BxPC-3 cells with IC50 concentrations of MM134, -6, and -9 compounds. However, no DNA fragmentation characteristics for apoptosis were observed in the flow cytometry and DNA laddering analysis. Gene expression data indicated up-regulation of BCL10, GADD45A, RIPK2, TNF, TNFRSF10B, and TNFRSF1A (TNF-R1) following treatment of cells with the MM134 compound. Moreover, in silico studies indicated AKT2 kinase as the primary target of compounds. MM-compounds exhibit strong cytotoxic activity with pro-oxidative, pro-apoptotic, and possibly pro-necroptotic properties that could be employed for further drug discovery approaches.


Assuntos
Antineoplásicos , Triazinas , Linhagem Celular Tumoral , Triazinas/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/farmacologia , Apoptose , Caspases/metabolismo , Sulfanilamida/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Estrutura Molecular , Relação Estrutura-Atividade
5.
Molecules ; 28(22)2023 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-38005180

RESUMO

The aim of this study was to determine the relationship between antioxidant and anticancer properties of extracts from blackcurrant (Ribes nigrum L.) leaves and their fractions and chemical contents. Dried ethanolic extract was divided into three fractions using solid phase extraction: aqueous (F1), 40% MeOH (F2), and 70% MeOH (F3). Both the extract and the fractions were analyzed in terms of antiradical activity (DPPH• and ABTS+•), total phenolic compounds, and total flavonoids. The antitumor potential of the fractions was evaluated in vitro on human colorectal (HCT 116) and prostate (PC-3) cancer cells. Phenolics were identified using HPLC-QTOF-MS, and twelve compounds were quantified by HPLC-DAD. Finally, principal component analysis was carried out to assess the relationship between the tested factors. The results confirmed that blackcurrant leaves are a rich source of phenolics with high antioxidant activity and anticancer properties. It was demonstrated that the F2 fraction had the highest content of phenolics and the highest antiradical activity. Additionally, only this fraction showed cytotoxic activity against HCT 116 cells. It was confirmed that both the blackcurrant leaf extract and its fractions are a promising source of condensed active compounds and can be used as natural functional food additives.


Assuntos
Ribes , Humanos , Ribes/química , Fenóis/farmacologia , Fenóis/análise , Antioxidantes/farmacologia , Antioxidantes/química , Flavonoides/farmacologia , Etanol , Extratos Vegetais/farmacologia , Extratos Vegetais/química
6.
Molecules ; 28(20)2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37894709

RESUMO

Multicomponent reactions have emerged as an important approach for the synthesis of diverse and complicated chemical compounds. They have various advantages over two-component reactions, including the convenience of one-pot procedures and the ability to modify the structure of agents. Here, we employed in vitro and in silico studies to explore the anticancer potential of novel aminobenzylnaphthols derived from the Betti reaction (MMZ compounds). MTT assay was used to explore the cytotoxic activity of the compounds in pancreatic (BxPC-3 cells) and colorectal (HT-29) cancer cell lines or normal human lung fibroblasts (WI-38 cells). Proapoptotic properties of two derivatives MMZ-45AA and MMZ-140C were explored using AO/EB and annexin V-FITC/PI staining. In silico studies including ADMET profiling, molecular target prediction, docking, and dynamics were employed. The compounds exhibited cytotoxic properties and showed proapoptotic properties in respective IC50 concentrations. As indicated by in silico investigations, anticancer activity of MMZs can be attributed to the inhibition of ADORA1, CDK2, and TRIM24. Furthermore, compounds exhibited favorable ADMET properties. MMZs constitute an interesting scaffold for the potential development of new anticancer agents.


Assuntos
Antineoplásicos , Benzaldeídos , Humanos , Benzaldeídos/farmacologia , Antineoplásicos/química , Células HT29 , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Proliferação de Células , Linhagem Celular Tumoral , Proteínas de Transporte/metabolismo
7.
Molecules ; 28(13)2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37446908

RESUMO

Cellular signaling pathways involved in the maintenance of the equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most abundant phenolic compound found in green tea. It has been shown to regulate multiple crucial cellular signaling pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, and others. Deregulation of the abovementioned pathways is involved in the pathophysiology of cancer. It has been demonstrated that EGCG may exert anti-proliferative, anti-inflammatory, and apoptosis-inducing effects or induce epigenetic changes. Furthermore, preclinical and clinical studies suggest that EGCG may be used in the treatment of numerous disorders, including cancer. This review aims to summarize the existing knowledge regarding the biological properties of EGCG, especially in the context of cancer treatment and prophylaxis.


Assuntos
Catequina , Neoplasias , Humanos , Transdução de Sinais , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias/tratamento farmacológico , NF-kappa B/metabolismo , Chá , Catequina/farmacologia , Catequina/uso terapêutico , Apoptose
8.
J Enzyme Inhib Med Chem ; 37(1): 1278-1298, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35506234

RESUMO

Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with a release of the proton. CA, especially CAIX and CAXII isoforms gained the attention of many researchers interested in anticancer drug design due to pivotal functions of enzymes in the cancer cell metastasis and response to hypoxia, and their expression restricted to malignant cells. This offers an opportunity to develop new targeted therapies with fewer side effects. Continuous efforts led to the discovery of a series of diverse compounds with the most abundant sulphonamide derivatives. Here we review current knowledge considering small molecule and antibody-based targeting of CAIX/CAXII in cancer.


Assuntos
Anidrases Carbônicas , Neoplasias , Anticorpos Monoclonais/farmacologia , Anidrase Carbônica IX/metabolismo , Anidrases Carbônicas/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Isoformas de Proteínas , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
9.
Int J Mol Sci ; 23(7)2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35408915

RESUMO

Cyclin-dependent kinases (CDKs) are pivotal mediators and effectors of the DNA damage response (DDR) that regulate both the pathway components and proteins involved in repair processes. Synthetic lethality (SL) describes a situation in which two genes are linked in such a way that the lack of functioning of just one maintains cell viability, while depletion of both triggers cell death. Synthetic lethal interactions involving CDKs are now emerging, and this can be used to selectively target tumor cells with DNA repair defects. In this review, SL interactions of CDKs with protooncogene products MYC, poly (ADP-ribose) polymerase (PARP-1), and cellular tumor antigen p53 (TP53) are discussed. The individual roles of each of the SL partners in DDR are described.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Mutações Sintéticas Letais , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Dano ao DNA/genética , Reparo do DNA , Poli(ADP-Ribose) Polimerases/metabolismo
10.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409206

RESUMO

Cancer is a leading cause of death worldwide. In many cases, the treatment of the disease is limited due to the metastasis of cells to distant locations of the body through the blood and lymphatic drainage. Most of the anticancer therapeutic options focus mainly on the inhibition of tumor cell growth or the induction of cell death, and do not consider the molecular basis of metastasis. The aim of this work is to provide a comprehensive review focusing on cancer metastasis and the mitogen-activated protein kinase (MAPK) pathway (ERK/JNK/P38 signaling) as a crucial modulator of this process.


Assuntos
Proteínas Quinases Ativadas por Mitógeno , Neoplasias , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Int J Mol Sci ; 23(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35682571

RESUMO

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides constitute a novel class of heterocyclic compounds with broad biological activity, including anticancer properties. Investigated in this study, MM-compounds (MM134, MM136, MM137, and MM139) exhibited cytotoxic and proapoptotic activity against cancer cell lines (BxPC-3, PC-3, and HCT-116) in nanomolar concentrations without causing cytotoxicity in normal cells (L929 and WI38). In silico predictions indicate that tested compounds exhibit favorable pharmacokinetic profiles and may exert anticancer activity through the inhibition of BTK kinase, the AKT-mTOR pathway and PD1-PD-L1 interaction. Our findings point out that these sulfonamide derivatives may constitute a source of new anticancer drugs after optimization.


Assuntos
Antineoplásicos , Sulfonamidas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Triazinas/farmacologia
12.
Molecules ; 27(12)2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35744887

RESUMO

In this paper, we present for the first time the evaluation of cytotoxicity and genotoxicity of de novo synthesized pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides MM129, MM130, and MM131 in human tumor cell lines: HeLa, HCT 116, PC-3, and BxPC-3. Cytotoxic and genotoxic properties of the tested compounds were estimated using the MTT assay, comet assay (alkaline and neutral version), and γ-H2AX immuno-staining. Examined sulfonamides exhibited strong anticancer properties towards tested cells in a very low concentration range (IC50 = 0.17-1.15 µM) after 72 h exposure time. The results of the alkaline and neutral version of the comet assay following 24 h incubation of the cells with tested compounds demonstrated the capability of heterocycles to induce significant DNA damage in exposed cells. HCT 116 cells were the most sensitive to the genotoxic activity of novel tricyclic pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides in the neutral version of the comet assay. Immunocytochemical detection of γ-H2AX showed an increase in DNA DSBs level in the HCT 116 cell line, after 24 h incubation with all tested compounds, confirming the results obtained in the neutral comet assay. Among all investigated compounds, MM131 showed the strongest cytotoxic and genotoxic activity toward all tested cell types. In conclusion, our results suggest that MM129, MM130, and MM131 exhibit high cytotoxic and genotoxic potential in vitro, especially towards the colorectal cancer cell line HCT 116. However, further investigations and analyses are required for their future implementation in the field of medicine.


Assuntos
Antineoplásicos , Triazinas , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaio Cometa , Dano ao DNA , Humanos , Sulfanilamida , Sulfonamidas/farmacologia , Triazinas/química , Triazinas/farmacologia
13.
Molecules ; 27(23)2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36500379

RESUMO

Coronavirus Disease-2019 (COVID-19) is a highly contagious disease caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) classified the disease a as global public health hazard on 11 March 2020. Currently, there are no adequate measures to combat viral infections, including COVID-19, and the medication guidelines for the management of COVID-19 are dependent on previous findings from SARS-CoV and MERS-CoV research. Natural products have achieved widespread acceptance around the world as a means of enhancing healthcare and disease prevention. Plants are a potential source of antiviral factors such as flavonoids, phenolic acids, terpenoids, and others. Some of these agents exhibit a broad spectrum of antiviral activity. This study aimed to screen herbal leads for possible inhibitors of the SARS-CoV-2 ADP Ribose Phosphatase enzyme (ARP). Guggulsterone was found to be highly stabilized within the active site of the viral ARP enzyme by molecular dynamic simulation with very little fluctuation throughout the simulation timeframe of 100 ns. Thus, guggulsterone can be further used to develop a safe and competent medication for evolving therapy against SARS-CoV-2 in post-preclinical and clinical trials.


Assuntos
COVID-19 , Coronavírus da Síndrome Respiratória do Oriente Médio , Humanos , SARS-CoV-2 , Adenosina Difosfato Ribose , Monoéster Fosfórico Hidrolases , Antivirais/química
14.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445393

RESUMO

In this article, a novel method of simultaneous carborane- and gadolinium-containing compounds as efficient agents for neutron capture therapy (NCT) delivery via magnetic nanocarriers is presented. The presence of both Gd and B increases the efficiency of NCT and using nanocarriers enhances selectivity. These factors make NCT not only efficient, but also safe. Superparamagnetic Fe3O4 nanoparticles were treated with silane and then the polyelectrolytic layer was formed for further immobilization of NCT agents. Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), energy dispersive X-ray (EDX), ultraviolet-visible (UV-Vis) and Mössbauer spectroscopies, dynamic light scattering (DLS), scanning electron microscopy (SEM), vibrating-sample magnetometry (VSM) were applied for the characterization of the chemical and element composition, structure, morphology and magnetic properties of nanocarriers. The cytotoxicity effect was evaluated on different cell lines: BxPC-3, PC-3 MCF-7, HepG2 and L929, human skin fibroblasts as normal cells. average size of nanoparticles is 110 nm; magnetization at 1T and coercivity is 43.1 emu/g and 8.1, respectively; the amount of B is 0.077 mg/g and the amount of Gd is 0.632 mg/g. Successful immobilization of NCT agents, their low cytotoxicity against normal cells and selective cytotoxicity against cancer cells as well as the superparamagnetic properties of nanocarriers were confirmed by analyses above.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro/farmacologia , Gadolínio/farmacologia , Boro/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Difusão Dinâmica da Luz , Gadolínio/química , Humanos , Células MCF-7 , Nanopartículas de Magnetita , Microscopia Eletrônica de Varredura , Células PC-3 , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
15.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500648

RESUMO

Ethanol extracts of two types of pepper (sweet and hot) were separated into fractions with increasing lipophilicity. After drying the extracts and fractions, their chemical composition, anti-radical activity in the DPPH radical system, and cytotoxic activity against PC-3 and HTC-116 cells were determined. A detailed qualitative analysis of the fractions was performed with the LC-QTOF-MS method. It was found that the chemical composition of pepper fractions did not always reflect their biological activity. The highest antiradical activity was detected in the fraction eluted with 40% methanol from sweet pepper. The highest total content of phenolic compounds was found in an analogous fraction from hot pepper, and this fraction showed the strongest cytotoxic effect on the PC-3 tumour line. The LC-MS analysis identified 53 compounds, six of which were present only in sweet pepper and four only in hot pepper. The unique chemical composition of the extracts was found to modulate their biological activity, which can only be verified experimentally.


Assuntos
Capsicum/química , Extratos Vegetais/química , Antioxidantes/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Fenóis/química , Piper nigrum/química , Verduras/química
16.
Beilstein J Org Chem ; 17: 558-568, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727979

RESUMO

Amino- and polyaminophthalazinones were synthesized by the palladium-catalyzed amination (alkyl- and arylamines, polyamines) of 4-bromophthalazinones in good yields. The coordinating properties of selected aminophthalazinones towards Cu(II) ions were investigated and the participation of the nitrogen atoms in the complexation of the metal ion was shown. A biological screening of the potential cytotoxicity of selected synthesized compounds on HT-29 and PC-3 cell lines, as well as on the L-929 cell line, proved that some amino derivatives of phthalazinone show interesting anticancer activities. The detailed synthesis, spectroscopic data, and biological assays are reported.

17.
Int J Mol Sci ; 21(9)2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32370233

RESUMO

Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains the main method for cancer treatment. Depending on the mechanism of action, commonly used chemotherapeutic agents can be divided into several classes (antimetabolites, alkylating agents, mitotic spindle inhibitors, topoisomerase inhibitors, and others). Multidrug resistance (MDR) is responsible for over 90% of deaths in cancer patients receiving traditional chemotherapeutics or novel targeted drugs. The mechanisms of MDR include elevated metabolism of xenobiotics, enhanced efflux of drugs, growth factors, increased DNA repair capacity, and genetic factors (gene mutations, amplifications, and epigenetic alterations). Rapidly increasing numbers of biomedical studies are focused on designing chemotherapeutics that are able to evade or reverse MDR. The aim of this review is not only to demonstrate the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment but also to present the mechanisms of action of novel potential antitumor drugs which have been designed to overcome these resistance mechanisms. Better understanding of the mechanisms of MDR and targets of novel chemotherapy agents should provide guidance for future research concerning new effective strategies in cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/classificação , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias/genética , Neoplasias/patologia , Farmacogenética/métodos
18.
Int J Mol Sci ; 21(14)2020 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-32664667

RESUMO

Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan's molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells' resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.


Assuntos
Irinotecano/uso terapêutico , Neoplasias/tratamento farmacológico , Pró-Fármacos/farmacocinética , Inibidores da Topoisomerase I/uso terapêutico , Ativação Metabólica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , DNA de Neoplasias/efeitos dos fármacos , Formas de Dosagem , Composição de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/farmacocinética , Masculino , Modelos Moleculares , Estrutura Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/enzimologia , Conformação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacocinética
19.
Int J Mol Sci ; 21(19)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019598

RESUMO

The protective ozone layer is continually depleting due to the release of deteriorating environmental pollutants. The diminished ozone layer contributes to excessive exposure of cells to ultraviolet (UV) radiation. This leads to various cellular responses utilized to restore the homeostasis of exposed cells. DNA is the primary chromophore of the cells that absorbs sunlight energy. Exposure of genomic DNA to UV light leads to the formation of multitude of types of damage (depending on wavelength and exposure time) that are removed by effectively working repair pathways. The aim of this review is to summarize current knowledge considering cellular response to UV radiation with special focus on DNA damage and repair and to give a comprehensive insight for new researchers in this field. We also highlight most important future prospects considering application of the progressing knowledge of UV response for the clinical control of diverse pathologies.


Assuntos
Ciclo Celular/efeitos da radiação , Reparo do DNA/efeitos da radiação , DNA/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Ciclo Celular/genética , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Dano ao DNA , Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/efeitos da radiação , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Dímeros de Pirimidina/química , Dímeros de Pirimidina/metabolismo , Transdução de Sinais , Ozônio Estratosférico/análise , Luz Solar/efeitos adversos
20.
Int J Mol Sci ; 21(11)2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32486270

RESUMO

Genomic DNA is constantly damaged by factors produced during natural metabolic processes as well as agents coming from the external environment. Considering such a wide array of damaging agents, eukaryotic cells have evolved a DNA damage response (DRR) that opposes the influence of deleterious factors. Despite the broad knowledge regarding DNA damage and repair, new areas of research are emerging. New players in the field of DDR are constantly being discovered. The aim of this study is to review current knowledge regarding the roles of sirtuins, heat shock proteins, long-noncoding RNAs and the circadian clock in DDR and distinguish new agents that may have a prominent role in DNA damage response and repair.


Assuntos
Dano ao DNA , Reparo do DNA , Animais , Ritmo Circadiano , DNA/metabolismo , Células Eucarióticas/metabolismo , Deleção de Genes , Genoma Humano , Proteínas de Choque Térmico/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Neoplasias/metabolismo , Biossíntese de Proteínas , RNA Longo não Codificante/metabolismo , Sirtuínas/metabolismo , Transcrição Gênica , Proteína Supressora de Tumor p53/metabolismo
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