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1.
BMC cancer ; 21(1): 575-678, May., 2021. ilus, graf, tab
Artigo em Inglês | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1224518

RESUMO

BACKGROUND: No biomarker is available for identifying cancer patients at risk of developing nephrotoxicity when treated with cisplatin. METHODS: We performed microRNA (miRNA) sequencing using plasma collected 5 days after cisplatin treatment (D5) from twelve patients with head and neck cancer with and without nephrotoxicity (grade ≥ 2 increased serum creatinine). The most differentially expressed miRNAs between the two groups were selected for quantification at baseline and D5 in a larger cohort of patients. The association between miRNAs and nephrotoxicity was evaluated by calculating the odds ratio (OR) from univariate logistic regression. Receiver operating characteristic curves (ROC) were used to estimate the area under the curve (AUC), sensitivity, and specificity. RESULTS: MiR-3168 (p = 1.98 × 10− 8 ), miR-4718 (p = 4.24 × 10− 5 ), and miR-6125 (p = 6.60 × 10− 5 ) were the most differentially expressed miRNAs and were further quantified in 43, 48, and 53 patients, respectively. The baseline expression of miR-3168 (p = 0.0456, OR = 1.03, 95% CI: 1.00­1.06) and miR-4718 (p = 0.0388, OR = 1.56, 95% CI: 1.03­ 2.46) were associated with an increased risk of nephrotoxicity, whereas miR-6125 showed a trend (p = 0.0618, OR = 1.73, 95% CI: 0.98­3.29). MiR-4718 showed the highest AUC (0.77, 95% CI: 0.61­0.93) with sensitivity of 66.76 and specificity of 79.49. CONCLUSIONS: We have provided evidence of baseline plasmatic expression of miR-3168, miR-6125, and miR-4718 as potential predictors of cisplatin-induced nephrotoxicity.


Assuntos
Cisplatino , MicroRNAs , Nefropatias , Neoplasias
2.
World J Gastroenterol ; 27(36): 6079-6092, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34629821

RESUMO

BACKGROUND: Gastric cancer is a prevalent malignant cancer with a high incidence and significantly affects the health of modern people globally. Cisplatin (DDP) is one of the most common and effective chemotherapies for patients with gastric cancer, but DDP resistance remains a severe clinical challenge. AIM: To explore the function of M2 polarized macrophages-derived exosomal microRNA (miR)-588 in the modulation of DDP resistance of gastric cancer cells. METHODS: M2 polarized macrophages were isolated and identified by specific markers using flow cytometry analysis. The exosomes from M2 macrophages were identified by transmission electron microscopy and related markers. The uptake of the PKH67-labelled M2 macrophages-derived exosomes was detected in SGC7901 cells. The function and mechanism of exosomal miR-588 from M2 macrophages in the modulation of DDP resistance of gastric cancer cells was analyzed by CCK-8 assay, apoptosis analysis, colony formation assay, Western blot analysis, qPCR analysis, and luciferase reporter assay in SGC7901 and SGC7901/DDP cells, and by tumorigenicity analysis in nude mice. RESULTS: M2 polarized macrophages were isolated from mouse bone marrow stimulated with interleukin (IL)-13 and IL-4. Co-cultivation of gastric cancer cells with M2 polarized macrophages promoted DDP resistance. M2 polarized macrophages-derived exosomes could transfer in gastric cancer cells to enhance DDP resistance. Exosomal miR-588 from M2 macrophages contributed to DDP resistance of gastric cancer cells. miR-588 promoted DDP-resistant gastric cancer cell growth in vivo. miR-588 was able to target cylindromatosis (CYLD) in gastric cancer cells. The depletion of CYLD reversed miR-588 inhibition-regulated cell proliferation and apoptosis of gastric cancer cells exposed to DDP. CONCLUSION: In conclusion, we uncovered that exosomal miR-588 from M2 macrophages contributes to DDP resistance of gastric cancer cells by partly targeting CYLD. miR-588 may be applied as a potential therapeutic target for the treatment of gastric cancer.


Assuntos
MicroRNAs , Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Macrófagos , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
3.
Anticancer Res ; 41(10): 4715-4718, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593419

RESUMO

BACKGROUND/AIM: Primary osteosarcoma of the breast is an exceedingly-rare malignant tumor that shares histological characteristics with osteosarcoma of the bone. Since effective therapies have not yet been established, standard therapy for osteosarcoma of the bone was examined in the present study for efficacy against primary osteosarcoma of the breast in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. MATERIALS AND METHODS: The PDOX mouse models were established by surgical implantation of the primary osteosarcoma of the breast specimen into the mammary gland of nude mice. Mice with tumors were randomized into four groups, each n=4: control group; cisplatinum (CDDP)-treatment group; doxorubicin (DOX)-treatment group; and CDDP/DOX-combination-treatment group. Mice were treated for twenty-one days, three weeks after implantation. Tumor size and body weight were measured during three weeks of treatment. RESULTS: Significant tumor growth inhibition was observed, compared to the control, in the CDDP-treatment group, the DOX-treatment group, and the combination-treatment-group. Only the combination treatment regressed the tumor. CONCLUSION: CDDP and DOX which are standard first-line therapies for osteosarcoma, may be clinically effective against primary osteosarcoma of the breast, and in particular, their combination.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Osteossarcoma/tratamento farmacológico , Animais , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 41(10): 5231-5240, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593476

RESUMO

BACKGROUND/AIM: The efficacy and feasibility of gemcitabine plus cisplatin (GC) chemotherapy in an adjuvant setting is unclear in patients with biliary tract cancer (BTC) undergoing major hepatectomy. PATIENTS AND METHODS: Patients with BTC who underwent major hepatectomy between 2008 and 2018 were included. Patients who received adjuvant chemotherapy (AC) were then divided into two groups: a GC group and a gemcitabine (GEM) alone group. AC-related factors and patient outcomes were investigated. RESULTS: Fifty (GC: 28, GEM: 22) patients received AC, and 33 patients did not. No difference in completion rate, relative dose intensity, or adverse events was seen between the two AC groups. Multivariate analysis revealed that AC with GC was an independent predictor of improved survival and reduction of early recurrence. CONCLUSION: AC with GC is tolerable and associated with better outcomes in patients with BTC who have undergone major hepatectomy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Quimioterapia Adjuvante/mortalidade , Hepatectomia/mortalidade , Adulto , Idoso , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/cirurgia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
5.
Ann Palliat Med ; 10(8): 9025-9038, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488389

RESUMO

BACKGROUND: Cisplatin has been a vital drug used for tumor treatment because of its excellent effect on numerous malignant solid cancers. Nonetheless, its nephrotoxicity is non-negligible in clinical practice. This study aims to provide a new understanding of the molecular mechanism of transient receptor potential ankyrin 1 (TRPA1) in cisplatin-induced renal apoptosis. METHODS: We evaluated the effect on apoptosis, TRPA1 expression, and intracellular calcium concentration of human kidney 2 (HK-2) cells induced by diamminedichloroplatinum (DDP). Additionally, we also assessed DDP-induced apoptosis, the expression of Bax, caspase3, cleaved-cas3, p53, Bcl-2 and intracellular calcium concentration combined with HC-030031 and/or pifithrin-α. The effect of FK506 on apoptosis of HK-2 cells induced by DDP and the expression of the nuclear factor of activated T cells (NFAT) protein treated with HC-030031, pifithrin-α, and/or FK506 were also explored. RESULTS: The results showed that apoptosis, TRPA1 expression, and intracellular calcium concentration of HK-2 cell induced by DDP were enhanced in a dose-dependent manner. HC-030031 and pifithrin-α relieved apoptosis, and intracellular calcium concentration and the expression of NFAT and phospho-NFAT (p-NFAT) were induced by DDP. HC-030031 combined with pifithrin-α further aggravated the above-mentioned tendency, including relieved apoptosis, intracellular calcium concentration, and NFAT and p-NFAT expression. HC-030031 and FK506 decelerated the apoptosis, and NFAT and p-NFAT expression of HK-2 cells was induced by DDP, while simultaneous treatment with HC-030031 and FK506 further decreased apoptosis and protein expression. However, the expression of Bcl-2 increased when HC-030031, pifithrin-α, or FK506 was used alone, and HC-030031 combined with pifithrin-α or FK506 further improved the expression of Bcl-2. CONCLUSIONS: TRPA1 mediates cisplatin-induced apoptosis in renal tubular cells via the calcineurin-nuclear factor of activated T-cells-p53 signaling pathway.


Assuntos
Apoptose , Cálcio , Cisplatino , Túbulos Renais/citologia , Transdução de Sinais , Canal de Cátion TRPA1/metabolismo , Linhagem Celular , Cisplatino/farmacologia , Humanos
6.
Braz J Biol ; 83: e243438, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34468509

RESUMO

Cisplatin (CP) is a commonly used, powerful antineoplastic drug, having numerous side effects. Casticin (CAS) is considered as a free radical scavenger and a potent antioxidant. The present research was planned to assess the curative potential of CAS on CP persuaded renal injury in male albino rats. Twenty four male albino rats were distributed into four equal groups. Group-1 was considered as a control group. Animals of Group-2 were injected with 5mg/kg of CP intraperitoneally. Group-3 was co-treated with CAS (50mg/kg) orally and injection of CP (5mg/kg). Group-4 was treated with CAS (50mg/kg) orally throughout the experiment. CP administration substantially reduced the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione S-transferase (GST), glutathione reductase (GSR), glutathione (GSH) content while increased thiobarbituric acid reactive substances (TBARS), and hydrogen peroxide (H2O2) levels. Urea, urinary creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, albumin and creatinine clearance was significantly reduced in CP treated group. The results demonstrated that CP significantly increased the inflammation indicators including nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activity and histopathological damages. However, the administration of CAS displayed a palliative effect against CP-generated renal toxicity and recovered all parameters by bringing them to a normal level. These results revealed that the CAS is an effective compound having the curative potential to counter the CP-induced renal damage.


Assuntos
Cisplatino , Peróxido de Hidrogênio , Animais , Antioxidantes , Cisplatino/toxicidade , Flavonoides , Masculino , Estresse Oxidativo , Ratos , Superóxido Dismutase/metabolismo
7.
Anal Chim Acta ; 1177: 338797, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34482885

RESUMO

Single cell - tandem ICP-mass spectrometry (SC-ICP-MS/MS) was used for the determination of the absolute amount of Pt (coming from exposure to various concentration levels of cisplatin as a chemotherapeutic drug) and five endogenous elements (P, S, Fe, Cu and Zn) in individual human cells of three different types - Raji, Jurkat and Y79. Optimum conditions were obtained by using a sample introduction unit transporting cell suspension containing approx. 5 × 104 cells per mL at a flow rate of 10 µL min-1 to a nebulizer with narrow internal diameter (250 µm i.d.), mounted onto a total consumption spray chamber. Interference-free conditions were obtained in tandem MS mode (i) for P and S by pressurizing the collision/reaction cell (CRC) with O2 and monitoring the PO+ and SO + reaction product ions and (ii) for Fe by pressurizing the CRC with NH3 and monitoring the Fe(NH3)2+ reaction product ion. The quantification approach was validated by comparison of the absolute amounts of the target elements (in fg per cell) as obtained using SC-ICP-MS/MS with those obtained after acid digestion of approx. 2 × 106 cells and subsequent solution ICP-MS/MS analysis ("bulk" analysis). A higher Pt cell content was observed upon increasing the concentration of the cisplatin solution the cells were exposed to during 24 h. The Pt mass per cell (fg) increased linearly as a function of the cisplatin concentration, but a higher Pt uptake was found in the case of Jurkat cells compared to the other cell types. A cell viability assay showed a lack of chemosensitivity to cisplatin below 200 µM for the Raji and Y79 cell line, but an IC50 value of 11.1 ± 1.3 µM for Jurkat cells. This difference in chemo-responsiveness between the different cell types supported the difference in Pt uptake as indicated via SC-ICP-MS analysis. The increasing level of Pt did not have a marked effect on the contents of the endogenous elements monitored in Raji and Y79 cells, but a decrease in the P and S cell content upon increasing cisplatin treatment was observed for Jurkat cells. This can most likely be attributed to stress induced by the chemotherapeutic treatment in cells showing chemosensitivity towards cisplatin. The results also indicate differences in the absolute amount of endogenous element per cell between different cell types, suggesting the potential of SC-ICP-MS as a "metallo-fingerprinting" tool.


Assuntos
Preparações Farmacêuticas , Espectrometria de Massas em Tandem , Cisplatino , Humanos , Análise Espectral
8.
Anticancer Res ; 41(9): 4277-4285, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475047

RESUMO

BACKGROUND/AIM: To evaluate the antitumor effects of Plitidepsin against clear cell carcinoma (CCC) of the ovary. MATERIALS AND METHODS: The expression of eEF1A2 in ovarian cancer was assessed by immunohistochemistry. Using ovarian CCC cell lines, the antitumor effect of Plitidepsin was assessed both in vitro and in vivo. By over-expressing or knocking down the eEF1A2 expression, we investigated the role of eEF1A2 in the sensitivity of CCC cells to Plitidepsin. RESULTS: Immunoreactivity to eEF1A2 was observed in 76.2% of CCC, which was significantly higher than other histological subtypes of ovarian cancer. Plitidepsin exhibited significant antitumor activity toward chemonaive and chemoresistant CCC cells both in vitro and in vivo. Ectopic expression of eEF1A2 in CCC cells resulted in increased sensitivity to Plitidepsin. In contrast, eEF1A2 knockdown decreased sensitivity of CCC cells to plitidepsin. CONCLUSION: Plitidepsin, a novel anti-cancer agent that targets eEF1A2, may be a promising agent for treating ovarian CCC.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Depsipeptídeos/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Fator 1 de Elongação de Peptídeos/metabolismo , Peptídeos Cíclicos/administração & dosagem , Regulação para Cima/efeitos dos fármacos , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino , Depsipeptídeos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fator 1 de Elongação de Peptídeos/genética , Peptídeos Cíclicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
BMC Cancer ; 21(1): 1061, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34565342

RESUMO

BACKGROUND: Neuroblastoma (NB) patients with MYCN amplification or overexpression respond poorly to current therapies and exhibit extremely poor clinical outcomes. PI3K-mTOR signaling-driven deregulation of protein synthesis is very common in NB and various other cancers that promote MYCN stabilization. In addition, both the MYCN and mTOR signaling axes can directly regulate a common translation pathway that leads to increased protein synthesis and cell proliferation. However, a strategy of concurrently targeting MYCN and mTOR signaling in NB remains unexplored. This study aimed to investigate the therapeutic potential of targeting dysregulated protein synthesis pathways by inhibiting the MYCN and mTOR pathways together in NB. METHODS: Using small molecule/pharmacologic approaches, we evaluated the effects of combined inhibition of MYCN transcription and mTOR signaling on NB cell growth/survival and associated molecular mechanism(s) in NB cell lines. We used two well-established BET (bromodomain extra-terminal) protein inhibitors (JQ1, OTX-015), and a clinically relevant mTOR inhibitor, temsirolimus, to target MYCN transcription and mTOR signaling, respectively. The single agent and combined efficacies of these inhibitors on NB cell growth, apoptosis, cell cycle and neurospheres were assessed using MTT, Annexin-V, propidium-iodide staining and sphere assays, respectively. Effects of inhibitors on global protein synthesis were quantified using a fluorescence-based (FamAzide)-based protein synthesis assay. Further, we investigated the specificities of these inhibitors in targeting the associated pathways/molecules using western blot analyses. RESULTS: Co-treatment of JQ1 or OTX-015 with temsirolimus synergistically suppressed NB cell growth/survival by inducing G1 cell cycle arrest and apoptosis with greatest efficacy in MYCN-amplified NB cells. Mechanistically, the co-treatment of JQ1 or OTX-015 with temsirolimus significantly downregulated the expression levels of phosphorylated 4EBP1/p70-S6K/eIF4E (mTOR components) and BRD4 (BET protein)/MYCN proteins. Further, this combination significantly inhibited global protein synthesis, compared to single agents. Our findings also demonstrated that both JQ1 and temsirolimus chemosensitized NB cells when tested in combination with cisplatin chemotherapy. CONCLUSIONS: Together, our findings demonstrate synergistic efficacy of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients.


Assuntos
Acetanilidas/farmacologia , Azepinas/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazóis/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Regulação para Baixo , Sinergismo Farmacológico , Fator de Iniciação 4E em Eucariotos/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Esferoides Celulares/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo
10.
Phys Chem Chem Phys ; 23(38): 21959-21971, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34569570

RESUMO

Cisplatin, (NH3)2PtCl2, has been known as a successful metal-based anticancer drug for more than half a century. Its analogue, Argplatin, arginine-linked cisplatin, (Arg)PtCl2, is being investigated because it exhibits reactivity towards DNA and RNA that differs from that of cisplatin. In order to understand the basis for its altered reactivity, the deprotonated and sodium cationized forms of Argplatin, [(Arg-H)PtCl2]- and [(Arg)PtCl2 + Na]+, are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy in the IR fingerprint and hydrogen-stretching regions. Complementary electronic structure calculations are performed using density functional theory approaches to characterize the stable structures of these complexes and to predict their infrared spectra. Comparison of the theoretical IR spectra predicted for various stable conformations of these Argplatin complexes to their measured IRMPD spectra enables determination of the binding mode(s) of Arg to the Pt metal center to be identified. Arginine is found to bind to Pt in a bidentate fashion to the backbone amino nitrogen and carboxylate oxygen atoms in both the [(Arg-H)PtCl2]- and [(Arg)PtCl2 + Na]+ complexes, the NO- binding mode. The neutral side chain of Arg also interacts with the Pt center to achieve additional stabilization in the [(Arg-H)PtCl2]- complex. In contrast, Na+ binds to both chlorido ligands in the [(Arg)PtCl2 + Na]+ complex and the protonated side chain of Arg is stabilized via hydrogen-bonding interactions with the carboxylate moiety. These findings are consistent with condensed-phase results, indicating that the NO- binding mode of arginine to Pt is preserved in the electrospray ionization process even under variable pH and ionic strength.


Assuntos
Antineoplásicos/química , Arginina/química , Cisplatino/química , Óxido Nítrico/química , Platina/química , Sítios de Ligação , Teoria da Densidade Funcional , Estrutura Molecular , Espectrofotometria Infravermelho
11.
BMC Cancer ; 21(1): 1003, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34493236

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. However, the molecular mechanism of resistance to platinum drug remains unknown. Endoplasmic reticulum resident protein 44(ERp44), an unfolded protein response (UPR)-induced endoplasmic reticulum(ER) protein, is induced during ER stress. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC. METHODS: Western blot and immunohistochemistry were used to investigate the expression of ERp44 and Glucose-Regulated Protein 78(GRP78) in NPC. We took CCK8 to detect the role of ERp44 on cell chemosensitivity. Flow cytometric analysis and western blot were taken to analyze cell apoptosis. We performed differential centrifugation to isolate exosomes from serum or conditioned media of cells and analyzed the impact of exosomal ERp44 on cells cisplatin sensitivity. Finally, the results were confirmed in vivo. RESULTS: We found the increased expression of ERp44 and GRP78 in NPC and ERp44 was highly expressed in ER-stressed tissues. Cell proliferation was inhibited after cisplatin treatment when ERp44 was knocked down and ERp44 strengthened cisplatin resistance by influencing cell apoptosis and pyroptosis. Then we also collected exosomes and cell viability was increased after the addition of NPC-derived-exosomes with cisplatin treatment. More importantly, our results showed under ERS, NPC cells secreted exosomes containing ERp44 and could transfer them to adjacent cells to strengthen chemoresistance. CONCLUSION: Our data suggested that exosomal ERp44 derived from ER-stressed NPC cells took an inevitable role in NPC chemoresistance and might act as a treatment target.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático , Exossomos/metabolismo , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Carcinoma Nasofaríngeo/tratamento farmacológico , Resposta a Proteínas não Dobradas , Animais , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Exossomos/genética , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Chaperonas Moleculares/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Int Med Res ; 49(9): 3000605211047077, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34579594

RESUMO

Squamous cell carcinoma (SCC) is a malignant epithelial tumor originating from the bronchial epithelium that shows keratosis and/or intercellular bridges. Papillary squamous cell carcinoma (PSCC) is an extremely rare subtype of SCC that manifests with a unique intrabronchial papillary growth pattern. Surgical resection is still the first recommendation for localized noninvasive SCC. However, some patients are not candidates for surgical resection. With the development of interventional pulmonology, bronchoscopic interventional therapy has played a key role in the treatment of central airway tumors. Here, we report a case of noninvasive PSCC in the airway treated with an electric snare, argon plasma coagulation (APC), and cryotherapy. After removing the tumor by electrotomy, cryotherapy, and APC, the tumor was injected with Endostar 15 mg (3 ml) and cisplatin 20 mg (diluted to 3 ml with 0.9% normal saline) in six separate sites, once every 21 days. The tumor was eliminated, and the treatment was stopped after four treatment cycles. During the 1-year follow-up, there was no recurrence of PSCC in the airway. In this case, submucosal injections of Endostar combined with cisplatin was a feasible and effective endoscopic method for treating a low-grade intratracheal malignant tumor.


Assuntos
Carcinoma de Células Escamosas , Cisplatino , Broncoscopia , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Endostatinas , Humanos , Injeções Intralesionais , Recidiva Local de Neoplasia , Proteínas Recombinantes , Estudos Retrospectivos
13.
BMJ Open ; 11(9): e045946, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493506

RESUMO

INTRODUCTION: The COVID-19 pandemic has driven unprecedented social and economic reform in efforts to curb the impact of disease. Governments worldwide have legislated non-essential service shutdowns and adapted essential service provision in order to minimise face-to-face contact. We anticipate major consequences resulting from such policies, with marginalised populations expected to bear the greatest burden of such measures, especially those with substance use disorders (SUDs). METHODS AND ANALYSIS: We aim to conduct (1) a scoping review to summarise the available evidence evaluating the impact of the COVID-19 pandemic on patients with SUDs, and (2) an evidence map to visually plot and categorise the current available evidence evaluating the impact of COVID-19 on patients with SUDs to identify gaps in addressing high-risk populations. ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review as we plan to review publicly available data. This is part of a multistep project, whereby we intend to use the findings generated from this review in combination with data from an ongoing prospective cohort study our team is leading, encompassing over 2000 patients with SUDs receiving medication-assisted therapy in Ontario prior to and during the COVID-19 pandemic.


Assuntos
COVID-19 , Transtornos Relacionados ao Uso de Substâncias , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Doxorrubicina , Humanos , Mitomicina , Pandemias , Estudos Prospectivos , SARS-CoV-2 , Transtornos Relacionados ao Uso de Substâncias/epidemiologia
14.
Phys Chem Chem Phys ; 23(36): 20533-20540, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34505588

RESUMO

We extend for the first time a quantum mechanical energy decomposition analysis scheme based on deformation electron densities to a hybrid electrostatic embedding quantum mechanics/molecular mechanics framework. The implemented approach is applied to characterize the interactions between cisplatin and a dioleyl-phosphatidylcholine membrane, which play a key role in the permeation mechanism of the drug inside the cells. The interaction energy decomposition into electrostatic, induction, dispersion and Pauli repulsion contributions is performed for ensembles of geometries to account for conformational sampling. It is evidenced that the electrostatic and repulsive components are predominant in both polar and non-polar regions of the bilayer.


Assuntos
Antineoplásicos/química , Cisplatino/química , Fosfatidilcolinas/química , Teoria Quântica , Modelos Moleculares , Estrutura Molecular
15.
JAMA ; 326(10): 916-925, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34519801

RESUMO

Importance: Standard first-line therapy for advanced or metastatic esophageal carcinoma is chemotherapy, but the prognosis remains poor. Camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) showed antitumor activity in previously treated advanced or metastatic esophageal squamous cell carcinoma. Objective: To evaluate the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as a first-line treatment in advanced or metastatic esophageal squamous cell carcinoma. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (ESCORT-1st study) enrolled patients from 60 hospitals in China between December 3, 2018, and May 12, 2020 (final follow-up, October 30, 2020). A total of 751 patients were screened and 596 eligible patients with untreated advanced or metastatic esophageal squamous cell carcinoma were randomized. Interventions: Patients were randomized 1:1 to receive either camrelizumab 200 mg (n = 298) or placebo (n = 298), combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were given intravenously every 3 weeks. Main Outcomes and Measures: Coprimary end points were overall survival (significance threshold, 1-sided P < .02) and progression-free survival (significance threshold, 1-sided P < .005). Results: Of the 596 patients randomized (median age, 62 years [interquartile range, 56-67 years]; 523 men [87.8%]), 1 patient in the placebo-chemotherapy group did not receive planned treatment. A total of 490 patients (82.2%) had discontinued the study treatment. The median follow-up was 10.8 months. The overall survival for the camrelizumab-chemotherapy group was a median of 15.3 months (95% CI, 12.8-17.3; 135 deaths) vs a median of 12.0 months (95% CI, 11.0-13.3; 174 deaths) for the placebo-chemotherapy group (hazard ratio [HR] for death, 0.70 [95% CI, 0.56-0.88]; 1-sided P = .001). Progression-free survival for camrelizumab plus chemotherapy was a median of 6.9 months (95% CI, 5.8-7.4; 199 progression or deaths) vs 5.6 months (95% CI, 5.5-5.7; 229 progression or deaths) for the placebo-chemotherapy group (HR for progression or death, 0.56 [95% CI, 0.46-0.68]; 1-sided P < .001). Treatment-related adverse events of grade 3 or higher occurred in 189 patients (63.4%) in the camrelizumab-chemotherapy group and 201 (67.7%) in the placebo-chemotherapy group, including treatment-related deaths among 9 patients (3.0%) and 11 patients (3.7%), respectively. Conclusions and Relevance: Among patients with advanced or metastatic esophageal squamous cell carcinoma, the addition of camrelizumab to chemotherapy, compared with placebo and chemotherapy, significantly improved overall survival and progression-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03691090.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Método Duplo-Cego , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Placebos , Intervalo Livre de Progressão , Qualidade de Vida , Análise de Sobrevida
16.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34518373

RESUMO

Dendritic cells (DC), macrophages, and monocytes, collectively known as mononuclear phagocytes (MPs), critically control tissue homeostasis and immune defense. However, there is a paucity of models allowing to selectively manipulate subsets of these cells in specific tissues. The steady-state adult kidney contains four MP subsets with Clec9a-expression history that include the main conventional DC1 (cDC1) and cDC2 subtypes as well as two subsets marked by CD64 but varying levels of F4/80. How each of these MP subsets contributes to the different phases of acute kidney injury and repair is unknown. We created a mouse model with a Cre-inducible lox-STOP-lox-diphtheria toxin receptor cassette under control of the endogenous CD64 locus that allows for diphtheria toxin-mediated depletion of CD64-expressing MPs without affecting cDC1, cDC2, or other leukocytes in the kidney. Combined with specific depletion of cDC1 and cDC2, we revisited the role of MPs in cisplatin-induced kidney injury. We found that the intrinsic potency reported for CD11c+ cells to limit cisplatin toxicity is specifically attributed to CD64+ MPs, while cDC1 and cDC2 were dispensable. Thus, we report a mouse model allowing for selective depletion of a specific subset of renal MPs. Our findings in cisplatin-induced injury underscore the value of dissecting the functions of individual MP subsets in kidney disease, which may enable therapeutic targeting of specific immune components in the absence of general immunosuppression.


Assuntos
Injúria Renal Aguda/prevenção & controle , Células Dendríticas/imunologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Macrófagos/imunologia , Monócitos/imunologia , Fagócitos/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Monócitos/patologia , Fagócitos/citologia , Receptores de IgG
17.
Anal Chim Acta ; 1181: 338920, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34556207

RESUMO

Drug resistance poses an enormous challenge for successful chemotherapy. Glutathione S-transferase (GST) has been confirmed to be involved in the progression of drug resistance to some anticancer drugs, thus revealing that the role of GST in anticancer drug resistance is necessary. Herein, by taking advantage of frequency upconversion luminescence (FUCL) technology, we reported an FUCL probe (NRh-NDs) that can detect GST based on a rhodamine derivative structure decorated with a 2,4-dinitrobenzenesulfonyl group (NDs). The NRh-NDs showed excellent sensitivity and high selectivity for GST and released the emissive dye NRh-NH2, which showed emission and excitation wavelengths in vitro of 820 nm and 850 nm, respectively. The NRh-NDs probe successfully tested endogenic GST in U87, MCF-7 and A549 cells. The cell data showed that the increased levels of GST were positively related to cisplatin resistance but not to 5-fluorouracil resistance. These results suggested that the probe could be used as a visual tool to reveal the cause of drug resistance for cisplatin resistance in cancer treatment. Furthermore, it may serve as an effective tool to confirm the mechanism of antitumor drug resistance.


Assuntos
Antineoplásicos , Preparações Farmacêuticas , Células A549 , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistência a Medicamentos , Glutationa , Glutationa Transferase , Humanos , Células MCF-7
18.
World J Surg Oncol ; 19(1): 280, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535176

RESUMO

BACKGROUND: This study was designed to probe into the effect of cisplatin combined with capecitabine on nasopharyngeal carcinoma (NPC). METHODS: A total of 136 NPC patients treated for the first time in our hospital from January 2016 to March 2017 were collected and divided into two groups: A and B. Among them, 66 in group A were treated with cisplatin intravenous drip, while 70 in group B were treated with capecitabine on the basis of group A. The efficacy, toxic and side effects, and quality of life of the two groups were observed. RESULTS: The short-term efficacy of group B was better than that of group A (p<0.05). The toxic and side effects of group B were lower than that of group A (p<0.05). The quality of life in group B was higher than that in group A (p<0.05). CONCLUSIONS: Cisplatin combined with capecitabine-induced chemotherapy for local NPC can improve the quality of life and reduce the toxic and side effects.


Assuntos
Cisplatino , Neoplasias Nasofaríngeas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Quimiorradioterapia , Cisplatino/efeitos adversos , Fluoruracila/efeitos adversos , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Prognóstico , Qualidade de Vida
19.
FASEB J ; 35(10): e21885, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478585

RESUMO

In a recently published phase III clinical trial, gemcitabine (GEM) plus cisplatin (DDP) induction chemotherapy significantly improved recurrence-free survival and overall survival and became the standard of care among patients with locoregionally advanced NPC. However, the molecular mechanisms of GEM synergized with DPP in NPC cells remain elucidated. These findings prompt us to explore the effect of the combination between GEM and DDP in NPC cell lines through proliferative phenotype, immunofluorescence, flow cytometry, and western blotting assays. In vitro studies reveal that GEM or DPP treated alone induces cell cycle arrest, promotes cell apoptosis, forces DNA damage response, and GEM synergism with DDP significantly increases the above effects in NPC cells. In vivo studies indicate that GEM or DPP treated alone significantly inhibits the tumor growth and prolongs the survival time of mice injected with SUNE1 cells compared to the control group. Moreover, the mice treated with GEM combined with DDP have smaller tumors and survive longer than those in GEM or DPP treated alone group. In addition, P-gp may be the key molecule that regulates the synergistic effect of gemcitabine and cisplatin. GEM synergizes with DPP to inhibit NPC cell proliferation and tumor growth by inducing cell cycle arrest, cell apoptosis, and DNA damage response, which reveals the mechanisms of combined GEM and DDP induction chemotherapy in improving locoregionally advanced NPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Cisplatino/agonistas , Cisplatino/farmacologia , Desoxicitidina/agonistas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nat Commun ; 12(1): 5421, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521823

RESUMO

MAD2L2 (REV7) plays an important role in DNA double-strand break repair. As a member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice by counteracting DNA end-resection. Here we investigated the requirements for shieldin complex assembly and activity. Besides a dimerization-surface, HORMA-domain protein MAD2L2 has the extraordinary ability to wrap its C-terminus around SHLD3, likely creating a very stable complex. We show that appropriate function of MAD2L2 within shieldin requires its dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction. Dimerization-defective MAD2L2 impairs shieldin assembly and fails to promote NHEJ. Moreover, MAD2L2 dimerization, along with the presence of SHLD3, allows shieldin to interact with the TRIP13 ATPase, known to drive topological switches in HORMA-domain proteins. We find that appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair. Together our data provide important insights in the dependencies for shieldin activity.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Proteínas de Ciclo Celular/genética , Reparo do DNA , Proteínas de Ligação a DNA/genética , DNA/genética , Proteínas Mad2/genética , ATPases Associadas a Diversas Atividades Celulares/química , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Animais , Sítios de Ligação , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/farmacologia , DNA/química , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Proteínas Mad2/química , Proteínas Mad2/metabolismo , Camundongos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
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