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1.
Medicine (Baltimore) ; 99(40): e22544, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019464

RESUMO

BACKGROUND: Clinical studies have shown that celecoxib can significantly inhibit the development of tumors, and basic experiments and in vitro experiments also provide a certain basis, but it is not clear how celecoxib inhibits tumor development in detail. METHODS: A literature search of all major academic databases was conducted (PubMed, China National Knowledge Internet (CNKI), Wan-fang, China Science and Technology Journal Database (VIP), including the main research on the mechanisms of celecoxib on tumors. RESULTS: Celecoxib can intervene in tumor development and reduce the formation of drug resistance through multiple molecular mechanisms. CONCLUSION: Celecoxib mainly regulates the proliferation, migration, and invasion of tumor cells by inhibiting the cyclooxygenases-2/prostaglandin E2 signal axis and thereby inhibiting the phosphorylation of nuclear factor-κ-gene binding, Akt, signal transducer and activator of transcription and the expression of matrix metalloproteinase 2 and matrix metalloproteinase 9. Meanwhile, it was found that celecoxib could promote the apoptosis of tumor cells by enhancing mitochondrial oxidation, activating mitochondrial apoptosis process, promoting endoplasmic reticulum stress process, and autophagy. Celecoxib can also reduce the occurrence of drug resistance by increasing the sensitivity of cancer cells to chemotherapy drugs.


Assuntos
Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Celecoxib/efeitos adversos , Celecoxib/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(5): 902-906, 2020 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-33047727

RESUMO

OBJECTIVE: To investigate the effects of salinomycin on the proliferation and apoptosis of oral squamous carcinoma cells and to further understand the mechanisms of these effects. METHODS: The human oral squamous carcinoma cell line CAL-27 was cultured in different concentrations of salinomycin and cisplatin. After co-culture with 0, 1, 2, 4, 8, 16 and 32 µmol/L salinomycin or 0, 1.25, 2.5, 5, 10, 20, 40 and 80 µmol/L cisplatin for 24 hours and 48 hours, the proliferation of oral squamous carcinoma cells were detected by cell counting kit-8(CCK-8) assay. After being exposed to 0, 2, 4, 8 µmol/L salinomycin and 0, 5, 10, 20 µmol/L cisplatin for 48 hours, the cell cycle of oral squamous carcinoma cells was detected by flow cytometry assay, and Western blot analysis was performed to analyze the expressions of cysteine-containing aspartate-specific proteases-3(Caspase-3), cysteine-containing aspartate-specific proteases-9(Caspase-9), poly ADP-ribose polymerase (PARP), protein kinase B (Akt) and phosphorylated protein kinase B (p-Akt) protein in oral squamous carcinoma cells. RESULTS: Both salinomycin and cisplatin significantly inhibited the proliferation of oral squamous cell carcinoma CAL-27 cells in a time- and dose-dependent manner. However, compared with the first-line chemotherapeutic drug cisplatin, salinomycin showed stronger anti-proliferation activity in oral squamous carcinoma cells than cisp-latin (P < 0.001). After being exposed to 8 µmol/L salinomycin, CAL-27 cells exhibited markedly higher proportion in quiescent/ first gap phases (40.40%±1.99% vs. 64.46%±0.90%, P < 0.05), and had a significantly lower proportion in synthesis phases and second gap / mitosis phases (24.32%±2.30% vs. 18.73%±0.61%, P < 0.05; 35.01%±1.24% vs. 16.54%±1.31%, P < 0.05) compared with the dimethyl sulfoxide control group; moreover cisplatin didn't show cell-cycle specific effect on CAL-27. Western blot proved that salinomycin could up-regulate the expressions of Caspase-3 and Caspase-9 protein in oral squamous cell carcinoma CAL-27 cells (P < 0.05). At the same time, the levels of PARP, Akt and p-Akt protein were down-regulated (P < 0.05). CONCLUSION: Compared with cisplatin, salinomycin has a better inhibitory effect on the proliferation of oral squamous carcinoma cells and blocks the cell cycle process at the quiescent / first gap phase. At the same time, salinomycin could trigger apoptosis of oral squamous carcinoma cells and the mechanism is associated with the Akt/p-Akt signaling pathway.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Bucais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Piranos
3.
Nat Commun ; 11(1): 4684, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943635

RESUMO

Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy. We show that autophagy is essential for tumor cells to cope with therapeutic perturbation of metabolism and that mTORC1-mediated suppression of autophagy is required and sufficient for generating a metabolic vulnerability leading to energy crisis and apoptosis. Our study links mTOR-induced cancer drug resistance to autophagy defects as a cause of a metabolic liability and opens a therapeutic window for the treatment of otherwise therapy-refractory tumor patients.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose , Tratamento Farmacológico , Feminino , Humanos , Neoplasias Pulmonares , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Medicine (Baltimore) ; 99(38): e22241, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957369

RESUMO

BACKGROUND: Quercetin, a major flavonol, wildly exists in plantage, which has been reported to have an anti-apoptosis and anti-inflammation effects on vascular endothelial cells, but its underlying molecular mechanisms remain unclear. OBJECTIVE: The aim of this study was to investigate the mechanisms of how quercetin inhibits tumor necrosis factor alpha (TNF-α) induced human umbilical vein endothelial cells (HUVECs) apoptosis and inflammation. METHODS AND RESULTS: HUVECs were preconditioned with quercetin for 18 hours, and subsequently treated with TNF-α for 6 hours to induce apoptosis. The expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, ß-actin mRNA was then detected by RT-PCR. Flow cytometry was used to estimate the apoptosis rates, and the expression of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) was measured by Western blot. TNF-α induced elevated apoptosis rates and upregulation of VCAM-1, ICAM-1, and E-selectin were meaningfully reduced in HUVECs by pretreatment with quercetin. In addition, quercetin also inhibited the activation of AP-1and NF-κB. CONCLUSION: Results indicate that quercetin could suppress TNF-α induced apoptosis and inflammation by blocking NF-κB and AP-1 signaling pathway in HUVECs, which might be one of the underlying mechanisms in treatment of coronary heart disease.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Inflamação/prevenção & controle , NF-kappa B/metabolismo , Quercetina/farmacologia , Fator de Transcrição AP-1/metabolismo , Regulação para Baixo , Selectina E/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
J Toxicol Sci ; 45(9): 549-558, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879254

RESUMO

Trimethyltin chloride (TMT) is a stabilizer by-product in the process of manufacturing plastic, which is a kind of very strong toxic substance, and has acute, cumulative and chronic toxicity. TMT may cause bradycardia in patients with occupational poisoning, the mechanism of which has not been reported. This study explored the mechanism of TMT resulting in bradycardia of C57BL/6 mice. TMT was administered to mice to measure heart rate, serum succinate dehydrogenase (SDH) level, and myocardial Na+/K+-ATPase activity and expression. The effects of TMT on myocardial apoptosis were observed by changing the expressions of caspase-3, Bax and Bcl-2 in myocardium. It was found that the heart rate and SDH activity in serum of mice gradually decreased with the increase of TMT dose compared with the control group. The activity and the expression of Na+/K+-ATPase in the heart tissue of mice exposed to TMT was measured and gradually decreased with the increase of dose and time. We measured the expression of Bcl-2, Bax, caspase-3 and cleaved caspase-3 in the heart tissues of TMT exposed mice and found that the expressions of Bax, caspase-3 and cleaved caspase-3 increased and the expressions of Bcl-2 decreased in the heart tissues of the TMT-exposed mice at different doses. With the extension of TMT exposure time, the expression of Bax and caspase-3 increased and the expression of Bcl-2 decreased in the heart tissues of TMT exposed mice. Our findings suggest the mechanisms of TMT resulting in bradycardia may be associated with the inhibited activity and decreased content of Na+/K+-ATPase, thus further leading to the changes of Bcl-2, Bax, caspase-3 and cleaved caspase-3 in the mice's ventricular tissues.


Assuntos
Apoptose/efeitos dos fármacos , Bradicardia/etiologia , Miocárdio/metabolismo , Miocárdio/patologia , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Trimetilestanho/toxicidade , Animais , Apoptose/genética , Bradicardia/genética , Caspase 3/genética , Caspase 3/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
6.
Clinics (Sao Paulo) ; 75: e1865, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935825

RESUMO

OBJECTIVES: Hypoxia leads to endothelial cell inflammation, apoptosis, and damage, which plays an important role in the complications associated with ischemic cardiovascular disease. As an oxidoreductase, p66Shc plays an important role in the regulation of reactive oxygen species (ROS) production and apoptosis. Ketamine is widely used in clinics. This study was designed to assess the potential protective effect of ketamine against hypoxia-induced injury in human umbilical vein endothelial cells (HUVECs). Moreover, we explored the potential mechanism by which ketamine protected against hypoxia-induced endothelial injury. METHODS: The protective effects of ketamine against hypoxia-induced injury was assessed using cell viability and adhesion assays, quantitative polymerase chain reaction, and western blotting. RESULTS: Our data showed that hypoxia reduced HUVEC viability, increased the adhesion between HUVECs and monocytes, and upregulated the expression of endothelial adhesion molecules at the protein and mRNA levels. Moreover, hypoxia increased ROS accumulation and upregulated p66Shc expression. Furthermore, hypoxia downregulated sirt1 expression in HUVECs. Alternatively, ketamine was shown to reverse the hypoxia-mediated reduction of cell viability and increase in the adhesion between HUVECs and monocytes, ameliorate hypoxia-induced ROS accumulation, and suppress p66Shc expression. Moreover, EX527, a sirt1 inhibitor, reversed the protective effects of ketamine against the hypoxia-mediated reduction of cell viability and increase in adhesion between HUVECs and monocytes. CONCLUSION: Ketamine reduces hypoxia-induced p66Shc expression and attenuates ROS accumulation via upregulating sirt1 in HUVECs, thus attenuating hypoxia-induced endothelial cell inflammation and apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Hipóxia , Ketamina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Estresse Oxidativo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Veias Umbilicais
7.
Life Sci ; 259: 118382, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898532

RESUMO

AIM: Vancomycin (VCM) is a glycopeptide antibiotic widely used to treat serious infections caused by methicillin-resistant Staphylococcus aureus and has been associated with some severe side effects such as hepatotoxicity and nephrotoxicity. However, the underlying mechanism of VCM-induced hepatotoxicity is not yet fully understood. Therefore, the current study was designed to evaluate the protective effects of zingerone (Zin) against VCM-induced hepatotoxicity in rats. MATERIALS AND METHODS: VCM was intraperitoneally administered at a dose of 200 mg/kg body weight (b.w.) for 7 days alone and in combination with the orally administered Zin (25 and 50 mg/kg b.w). KEY FINDINGS: Zin treatment significantly improved VCM-induced hepatic lipid peroxidation, glutathione depletion, reduced antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities and liver function markers (aspartate aminotransferase, alkaline phosphatase and alanine aminotransferase). Histopathological integrity and immunohistochemical expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the VCM-induced liver tissue were ameliorated after Zin administration. In addition, Zin reversed the changes in levels and/or activities of inflammatory and apoptotic parameters such as nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), p53, cysteine aspartate specific protease-3 (caspase-3), cysteine aspartate specific protease-8 (caspase-8), cytochrome c, Bcl-2 associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) in the VCM-induced hepatotoxicity. SIGNIFICANCE: Collectively, these results reveal probable ameliorative role of Zin against VCM-induced hepatotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Guaiacol/análogos & derivados , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Vancomicina/toxicidade , Animais , Western Blotting , Ciclo-Oxigenase 2/metabolismo , Guaiacol/uso terapêutico , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
8.
J Environ Pathol Toxicol Oncol ; 39(3): 281-290, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865918

RESUMO

Objective-To investigate cystathionine ß synthase (CBS)/hydrogen sulfide (H2S) signaling in multiple myeloma (MM) patients and to identify its effect on the proliferation of U266 cells. Methods-Bone marrow samples of 19 MM patients and 23 healthy donors were collected. qRT-PCR was performed to measure the mRNA expression levels of H2S synthases, cystathionine ß synthase, and cystathionine γ lyase. ELISA assays quantified the amount of H2S produced by the two enzymes CBS and CSE. CCK-8 experiment was used to investigate the influence of the CBS inhibitor amino oxyacetic acid and the CSE inhibitor propargylglycine on the proliferation of U266 cells. Flow cytometry and western blotting were performed to determine the effects of AOAA, PAG, and NaHS on cell cycle distribution as well as Caspase-3 and Bcl-2 expression. Results-Patients with MM had higher level of CBS compared with healthy donors. AOAA significantly inhibited cell proliferation in both a time and concentration dependent characteristic, whereas PAG does not. After 24 hours of treatment, AOAA significantly elevated the G0/G1 phase proportion of cells, and reduced the cell distribution in both S and G2/M phases, while NaHS accelerated cell cycle progression by reducing the relative number of cells in G0/G1 phase and increasing the proportion of cells in the G2/M phase. Moreover, AOAA abolished the impact of NaHS on cell cycle progression of U266 cells. AOAA treatment also led to a significant decrease in Bcl-2 expression and dramatic increase in Caspase-3 expression, though NaHS reversed these effects. Conclusion-CBS/H2S system might have a certain effect on the proliferation and apoptosis of MM cells.


Assuntos
Apoptose , Proliferação de Células , Cistationina beta-Sintase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Mieloma Múltiplo/metabolismo , Adulto , Idoso , Alquinos/farmacologia , Ácido Amino-Oxiacético/farmacologia , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Transdução de Sinais
9.
Oxid Med Cell Longev ; 2020: 8384742, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32963703

RESUMO

H2 has shown anti-inflammatory and antioxidant ability in many clinical trials, and its application is recommended in the latest Chinese novel coronavirus pneumonia (NCP) treatment guidelines. Clinical experiments have revealed the surprising finding that H2 gas may protect the lungs and extrapulmonary organs from pathological stimuli in NCP patients. The potential mechanisms underlying the action of H2 gas are not clear. H2 gas may regulate the anti-inflammatory and antioxidant activity, mitochondrial energy metabolism, endoplasmic reticulum stress, the immune system, and cell death (apoptosis, autophagy, pyroptosis, ferroptosis, and circadian clock, among others) and has therapeutic potential for many systemic diseases. This paper reviews the basic research and the latest clinical applications of H2 gas in multiorgan system diseases to establish strategies for the clinical treatment for various diseases.


Assuntos
Hidrogênio/administração & dosagem , Hidrogênio/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Betacoronavirus , Infecções por Coronavirus/terapia , Metabolismo Energético/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/terapia , Substâncias Protetoras/farmacologia
10.
Anticancer Res ; 40(10): 5379-5391, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988857

RESUMO

BACKGROUND/AIM: Hypoxia-inducible factor 1 (HIF1) inhibitors have been proposed as therapeutic agents for several tumor types. HIF1α is induced by hypoxia and by pathogens in normoxia through toll-like receptors (TLRs). The TLR3 activator polyinosinic:polycytidylic acid [poly(I:C)] induces apoptosis in various types of cancer but not in the most aggressive breast cancer cell lines. We hypothesized that the failure of TLR3 stimulation to induce apoptosis in these cells might be due to an elevated HIF1α level and this link might be exploited. MATERIALS AND METHODS: Poly(I:C)-induced signaling pathway and expression of HIF1α and HIF1α targets were studied in MDA MB-231 and MCF-7 breast cancer cell lines by western blot. Flow cytometry was used for apoptotic responses and vasculogenic mimicry as bioassay. RESULTS: Poly(I:C) increased expression of HIF1α and its targets BCL2 apoptosis regulator and c-MYC. Moreover, using pharmacological or genetic HIF1 inhibition, reduction of poly(I:C)-induced expression of HIF1α was paralleled by lowering of c-MYC and increased sensitivity to poly(I:C)-induced apoptosis, demonstrating the crucial role of this factor. We provide the first evidence in breast cancer cells that TLR3 stimulation induces HIF1α-dependent vasculogenic mimicry. By using specific inhibitors, we identified a signaling cascade upstream of HIF1α induction. CONCLUSION: Combined treatment with poly(I:C) and HIF1 inhibitors deserves consideration as an effective strategy in breast cancer therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Poli I-C/farmacologia , Receptor 3 Toll-Like/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/agonistas
11.
Anticancer Res ; 40(10): 5497-5502, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988872

RESUMO

BACKGROUND/AIM: The cell-killing and radiosensitizing effects of carbon-ion (C-ion) beams with low linear energy transfer (LET) are underexplored. We aimed to demonstrate the cell-killing effects of 60Co gamma rays and C-ion beams at various LET values and the radiosensitizing effect of C-ion beams at various LET and cisplatin levels. MATERIALS AND METHODS: Human uterine cervical cancer cells were irradiated with 60Co gamma rays and C-ion beams at different levels of LET, with and without cisplatin treatment. RESULTS: Low-LET C-ion beams had a superior cell-killing effect compared to 60Co gamma rays. Survival curves under low-LET C-ion beams were more similar to that of 60Co gamma rays than that of high-LET C-ion beams. Cisplatin significantly reduced cell survival after 1, 2, and 3 Gy C-ion beam irradiations at LET values of 13/30/70 keV/µm, 13/30 keV/µm, and 13 keV/µm, respectively. CONCLUSION: Low-LET C-ion beams combined with cisplatin have higher radiosensitizing effects than high-LET C-ion beams.


Assuntos
Carbono/uso terapêutico , Radioisótopos de Cobalto/uso terapêutico , Radiossensibilizantes/uso terapêutico , Neoplasias do Colo do Útero/radioterapia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Cisplatino/farmacologia , Relação Dose-Resposta à Radiação , Feminino , Raios gama , Humanos , Transferência Linear de Energia/efeitos da radiação , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
12.
Anticancer Res ; 40(10): 5517-5527, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988875

RESUMO

BACKGROUND/AIM: Drug resistance is a significant cause of high mortality in ovarian cancer (OC) patients. The reverse transcriptase inhibitor azidothymidine (AZT) has been utilized as a treatment for tumors, but its role in OC treatment has not been revealed. The aim of the present in vitro study was to examine the influence of AZT on the growth of human OC cells and the involved proteins. MATERIALS AND METHODS: The proliferation, cell cycle distribution, extent of apoptosis, mitotic index, and terminal restriction fragment length were examined in three OC cell lines, CaOV3, TOV112D, and TOV21G, treated with AZT. RESULTS: AZT inhibited growth of the TOV21G and CaOV3 cell lines by regulating cell cycle distribution. Specifically, AZT caused G2/M phase arrest on TOV21G cells and S phase arrest on CaOV3 cells. In addition, AZT treatment induced up-regulation of p21 and p16 in the TOV21G and CaOV3 cell line, respectively. CONCLUSION: AZT inhibited cell proliferation in serous and clear cell OC via the regulation of cell cycle distribution.


Assuntos
Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Zidovudina/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
13.
Anticancer Res ; 40(10): 5641-5647, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988888

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) have gained remarkable attention because of their ability to dualistically regulate tumor growth. The main objective of this study was to evaluate the apoptotic effects of human bone marrow-derived (hBM) MSCs in combination with interferon gamma (IFN-γ) on MCF-7 breast cancer cells, and to determine the cytokines involved in the apoptotic process. MATERIALS AND METHODS: hBM-MSCs were co-cultured with MCF-7 cells either directly and indirectly for 72 h in-vitro. Levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), apoptosis and cytokines were analyzed. RESULTS: hBM-MSCs increased the apoptosis of MCF-7 cells partially through TRAIL in vitro. IFN-γ enhanced the apoptotic effect of hBM-MSCs (p<0.001). CONCLUSION: hBM-MSCs in combination with IFN-γ might be a suitable therapy for breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Interferon gama/farmacologia , Células-Tronco Mesenquimais/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Técnicas de Cocultura , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon gama/genética , Células MCF-7 , Células-Tronco Mesenquimais/citologia
14.
PLoS Negl Trop Dis ; 14(8): e0008575, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866156

RESUMO

BACKGROUND: Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments. METHODOLOGY/PRINCIPAL: Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). FINDINGS: The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. CONCLUSIONS/SIGNIFICANCE: All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.


Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Suramina/farmacologia , Suramina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fosfoglicerato Quinase/efeitos dos fármacos , Células RAW 264.7/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
15.
Anticancer Res ; 40(9): 4829-4841, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878771

RESUMO

Most breast cancers express the estrogen receptor (ER) receptor and are negative for the human epidermal growth factor receptor 2 (HER2) receptor. ER+/HER2- cancers are treated with hormone-based therapies in the adjuvant setting and derive significant survival benefit from these therapies in the metastatic setting. However, hormone resistance develops in most metastatic patients. An increased understanding of the biology of ER+/HER2- breast cancers has led to the development of new therapies for this disease including CDK4/6 inhibitors and PI3K inhibitors. Several other neoplastic processes are targeted by novel drugs in clinical development, addressing cancer vulnerabilities. These include newer ways to block the ER and targeting the HER2 receptors in ER+/HER2- cancers expressing HER2 in low levels not qualifying for clinical positivity. In addition, promising therapeutic options include targeting other surface receptors or their downstream pathways, as well as targeting the apoptotic machinery and boosting the immune response which is initially insufficient in these cancers. A selection of new drugs in advanced development for ER+/HER2- breast cancer will be discussed in this review.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Anticancer Res ; 40(9): 4843-4856, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878772

RESUMO

Aberrant fatty acid (FA) metabolism has long been recognized in colorectal cancer (CRC) cells. Since de novo lipogenesis is required for CRC tumour growth and survival, the inhibition of FA metabolism is a promising potential therapeutic target. Inhibition of the opposite process, ß-oxidation of FAs, has also showed promising results in many CRC models. For patients with CRC, both FA synthesis and ß-oxidation inhibitors are promising potential therapeutic options as monotherapies or as combination therapies with other anticancer agents. In this review, we discuss recent reports concerning inhibitors of FA synthesis and ß-oxidation in various CRC models. The exact mechanisms of action of the selected compounds described in this review remain unknown and require precise evaluation before the development of new successful therapies for CRC is possible.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos
17.
Anticancer Res ; 40(9): 4885-4894, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878776

RESUMO

AIM: The aim of this study was to investigate the antitumor potential of guaiazulene-3-carboxylate derivatives against oral malignant cells. MATERIALS AND METHODS: Twelve guaiazulene-3-carboxylate derivatives were synthesized by introduction of either with alkyl group [1-5], alkoxy group [6, 7], hydroxyl group [8, 9] or primary amine [10-12] at the end of sidechains. Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against 3 human oral mesenchymal cell lines to that against 4 human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50value against OSCC cell lines. Cell cycle analysis was performed by cell sorter. RESULTS: [6, 7] showed the highest TS and PSE values, and induced the accumulation of both subG1 and G2/M cell populations in HSC-2 OSCC cells. Quantitative structure-activity relationship analysis demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the 3D shape, electric state and ionization potential. CONCLUSION: Alkoxyl guaiazulene-3-carboxylates [6, 7] can be potential candidates of lead compound for developing novel anticancer drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azulenos/química , Azulenos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Azulenos/síntese química , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias Bucais/patologia , Relação Quantitativa Estrutura-Atividade , Sesquiterpenos de Guaiano/síntese química
18.
Anticancer Res ; 40(9): 4907-4912, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878778

RESUMO

BACKGROUND/AIM: We investigated the effects of luteolin (LUT) on classical Hodgkin's lymphoma (cHL), since such studies in malignant lymphomas are lacking. MATERIALS AND METHODS: Effect of LUT on cell growth was assessed with water-soluble tetrazolium 1 (WST-1) cell proliferation assay and automated hemocytometry on trypan blue-exclusion assay. Cell death was investigated with acridine orange/ethidium bromide live-dead assay, propidium iodide (PI) flow cytometry, and Annexin-V-PI microscopy. Caspase activation was studied using CellEvent Caspase-3/7 Green detection reagent. High resolution immunofluorescence microscopy was used to detect cleaved-PARP-1. RESULTS: LUT induced a dose-dependent decrease in the growth of KMH2 and L428 cells, cellular models of mix-cellularity (MC) and nodular sclerosis (NS) cHL, respectively. However, LUT induced cell death only in KMH2, at a higher concentration, and this was associated with caspase activation and cleaved PARP-1. CONCLUSION: LUT induces cytotoxicity in the MC-cHL cellular model KMH2 via caspase activation.


Assuntos
Antineoplásicos/farmacologia , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Luteolina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Poli(ADP-Ribose) Polimerase-1/metabolismo
19.
Anticancer Res ; 40(9): 4947-4960, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878783

RESUMO

BACKGROUND/AIM: This study aimed to investigate the anticancer effects and potential mechanisms of sclareol in a human small cell lung carcinoma (SCLC) cell line. MATERIALS AND METHODS: Cell viability was determined by the MTT assay. Cell cycle, apoptosis and caspase activity were evaluated by flow cytometry. Cell cycle and DNA damage related protein expression was determined by western blotting. In vivo evaluation of sclareol was carried out in xenografted tumor mice models. RESULTS: Sclareol significantly reduced cell viability, induced G1 phase arrest and subsequently triggered apoptosis in H1688 cells. In addition, this sclareol-induced growth arrest was associated with DNA damage as indicated by phosphorylation of H2AX, activation of ATR and Chk1. Moreover, in vivo evaluation of sclareol showed that it could inhibit tumor weight and volume in a H1688 xenograft model. CONCLUSION: Sclareol might be a novel and effective therapeutic agent for the treatment of SCLC patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Diterpenos/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Anticancer Res ; 40(9): 4969-4978, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878785

RESUMO

BACKGROUND/AIM: Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis. RESULTS: The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05). CONCLUSION: BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brucea/química , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/patologia , Óleos Vegetais/uso terapêutico , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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