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BACKGROUND/AIM: Current NPC treatment methods have improved the 5-year survival rates of patients; however, some patients do not benefit from the treatments. Therefore, the existing treatment methods or new drugs must be developed to improve the patient's prognosis. NAD (P)H:quinone oxidoreductase 1 (NQO1), an electron reductase highly expressed in various cancers, can convert aziridinyl-substituted quinone-derived compound into an alkylating agent, resulting in cell apoptosis. Therefore, a di-aziridinyl-substituted quinone-derived compound, AZ-1, was designed previously. The present study investigated whether AZ-1 has anticancer activities in NPC cells and explored the underlying mechanism. MATERIALS AND METHODS: NPC-TW01 cells were used in the study, and 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide, colony formation, terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunoblotting assays were performed to assess the cell viability, cell survival, DNA fragmentation, and protein expression, respectively. RESULTS: The results show that AZ-1 significantly inhibited the viability and survival of NPC-TW01 cells. AZ-1 also induced the expression of cleaved PARP, cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3, and triggered DNA fragmentation in NPC-TW01 cells. In addition, AZ-1 induced γH2AX expression, a DNA damage marker, in NPC-TW01 cells. Treatment with dicoumarol, an NQO1 activity inhibitor, not only reversed AZ-1-induced cell viability inhibition but also decreased AZ-1-induced expression of γH2AX, cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3. CONCLUSION: NQO1 reverses AZ-1-triggered cell viability inhibition, DNA damage, and apoptosis. The findings of this study may provide a basis for the possible clinical application of AZ-1 in the treatment of NPC to improve the prognosis of patients with NPC.
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NAD(P)H Desidrogenase (Quinona) , NAD , Neoplasias Nasofaríngeas , Humanos , Caspase 3 , Caspase 8 , Caspase 9 , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Quinonas , NAD(P)H Desidrogenase (Quinona)/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismoRESUMO
(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1-YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.
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The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.
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The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.
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Neoplasias de Cabeça e Pescoço , Proteína Supressora de Tumor p53 , Proliferação de Células , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
In this study, the wear behavior of a heat-treatable Al-7Si-0.5Mg-0.5Cu alloy fabricated by selective laser melting was investigated systematically. Compared with the commercial homogenized AA2024 alloy, the fine secondary phase of the SLM Al-Cu-Mg-Si alloy leads to a low specific wear rate (1.8 ± 0.11 × 10-4 mm3(Nm)-1) and a low average coefficient of friction (0.40 ± 0.01). After the T6 heat treatment, the SLM Al-Cu-Mg-Si alloy exhibits a lower specific wear rate (1.48 ± 0.02 × 10-4 mm3(Nm)-1), but a similar average coefficient of friction (0.34 ± 0.01) as the heat-treated AA2024 alloy. Altogether, the SLM Al-3.5Cu-1.5Mg-1Si alloy is suitable for the achievement of not only superior mechanical performance, but also improved tribological properties.
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OBJECTIVE: To investigate the effect of antimalarials on cancer risk in patients with systemic lupus erythematosus (SLE). METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library were searched from their inception to October 3, 2020. Relative risk (RR) with 95% confidence intervals (CI) was used to evaluate the results. Subgroup analyses were used to assess heterogeneity. A funnel plot was used to explore publication bias. STATA was applied for all analyses. RESULTS: A total of nine studies consisted of four nested case-control, two case-cohort and three cohort studies were included. The results showed that antimalarials might reduce the risk of cancer in SLE (RR = 0.68, 95%CI: 0.55-0.85). In the subgroup analysis of four nested case-control and two case-cohort studies, the pooled RR was estimated as 0.69 (95% CI: 0.60-0.80). In four studies about hydroxychloroquine, the pooled RR was estimated as 0.70 (95% CI: 0.53-0.93). Antimalarials might reduce the risk of cancer in SLE among the Asian population (RR = 0.66; 95% CI: 0.49-0.88) (I2 = 43.1%, p = .173). And the consistent result was also found in SLE from multiple centres (RR = 0.72; 95%CI: 0.60-0.87) (I2 = 0%, p = .671). On disease course- and comorbidities-matched studies, the pooled RRs were 0.69 (95% CI: 0.52-0.93) and 0.59 (95% CI: 0.46-0.75), respectively. CONCLUSION: Results of this meta-analysis showed that antimalarial drugs might be protective factors for cancer in SLE. Hydroxychloroquine might be a protective factor for cancer in SLE patients.KEY MESSAGESAntimalarials might be protective factors for cancer in SLE.Hydroxychloroquine might be a protective factor for cancer in SLE patients.The first article to perform the meta-analysis of antimalarial drugs on the risk of cancer in SLE patients.