Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 351.193
Filtrar
1.
Braz. j. biol ; 83: e248746, 2023. graf
Artigo em Inglês | MEDLINE, LILACS, VETINDEX | ID: biblio-1339351

RESUMO

Abstract Colorectal cancer (CRC) is one of the most common cancers leading to comorbidities and mortalities globally. The rational of current study was to evaluate the combined epigallocatechin gallate and quercetin as a potent antitumor agent as commentary agent for therapeutic protocol. The present study investigated the effect of epigallocatechin Gallate (EGCG) (150mg) and quercetin (200mg) at different proportions on proliferation and induction of apoptosis in human colon cancer cells (HCT-116). Cell growth, colonogenic, Annexin V in addition cell cycle were detected in response to phytomolecules. Data obtained showed that, the colony formation was inhibited significantly in CRC starting from the lowest concentration tested of 10 µg/mL resulting in no colonies as visualized by a phase-contrast microscope. Data showed a significant elevation in the annexin V at 100 µg/mL EGCG(25.85%) and 150 µg/mL quercetin (48.35%). Moreover, cell cycle analysis showed that this combination caused cell cycle arrest at the G1 phase at concentration of 100 µg/mL (72.7%) and 150 µg/mL (75.25%). The combined effect of epigallocatechin Gallate and quercetin exert antiproliferative activity against CRC, it is promising in alternative conventional chemotherapeutic agent.


Resumo O câncer colorretal (CCR) é um dos cânceres mais comuns, levando a comorbidades e mortalidade em todo o mundo. O racional do presente estudo foi avaliar a combinação de galato de epigalocatequina e quercetina como um agente antitumoral potente como agente de comentário para protocolo terapêutico. O presente estudo investigou o efeito de galato de epigalocatequina (EGCG) (150 mg) e quercetina (200 mg) em diferentes proporções na proliferação e indução de apoptose em células de câncer de cólon humano (HCT-116). O crescimento celular, colonogênico, anexina V, além do ciclo celular foram detectados em resposta a fitomoléculas. Os dados obtidos mostraram que a formação de colônias foi inibida significativamente no CRC a partir da concentração mais baixa testada de 10 µg/mL, resultando em nenhuma colônia conforme visualizado por um microscópio de contraste de fase. Os dados mostraram uma elevação significativa na anexina V a 100 µg/mL de EGCG (25,85%) e 150 µg/mL de quercetina (48,35%). Além disso, a análise do ciclo celular mostrou que essa combinação causou parada do ciclo celular na fase G1 na concentração de 100 µg/mL (72,7%) e 150 µg/mL (75,25%). O efeito combinado da epigalocatequina galato e quercetina exerce atividade antiproliferativa contra o CCR, é promissor como agente quimioterápico alternativo convencional.


Assuntos
Humanos , Neoplasias Colorretais/tratamento farmacológico , Catequina/análogos & derivados , Catequina/farmacologia , Quercetina/farmacologia , Ciclo Celular , Anexina A5 , Linhagem Celular Tumoral , Proliferação de Células
2.
Cell Biol Int ; 46(4): 599-610, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34957655

RESUMO

In most cases of cervical cancer, the high risk of the disease is caused by the human papilloma virus (HPV). Surgery or radiation usually benefits patients with early cervical cancer, while the metastatic one is uncurable and new therapeutic strategies and approaches are required. In this study, HPV16 E6 silence or overexpression were carried out to evaluate the possible mechanisms of HPV16 E6 function in cervical cancer cells with different HPV16 E6 expression background. HPV16 E6-positive cervical cancer cell Siha exerts significantly stronger cell invasion and migration potentials than the HPV16 E6-negative C33A cells. HPV16 E6 silence significantly weakened the potentials of cell invasion and migration, cell proliferation and stemness characteristic in Siha cells. Meanwhile, the overexpression of HPV16 E6 effectively promoted the cell proliferation and stemness characteristic in C33A cells. Our data also indicated a positive association between HPV16 E6 and the levels of epithelial to mesenchymal transition (EMT), and cell stemness. The ectopic expression of OCT4 could effectively reverse the inhibitory roles of HPV16 E6 silence on cell migration, invasion, and stemness in Siha cells. More interestingly, we found that HPV16 E6 might promote the OCT4 expression by impairing the direct binding of p53 on the promoter and activate its transcription. Taken together, our results indicated that HPV16 E6 could promoted the potential cell proliferation, migration, and invasion of human cervical cancer cells by modulating EMT and cell stemness. Our data provide a novel mechanism for how HPV16 E6 acts as a key risk factor for cervical cancer development and progression.


Assuntos
Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Papillomavirus Humano 16/metabolismo , Humanos , Neoplasias do Colo do Útero/metabolismo
3.
Drug Dev Res ; 83(1): 208-216, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34347904

RESUMO

Breast cancer (BC), which is widely considered as the most common cancer in women around the world, evokes ~1.7 million new BC cases and 522,000 BC-related deaths each year. Triple negative breast cancer (TNBC) is clinically confirmed as one of the most aggressive subtypes of BC. ORY-1001, a clinically used lysine specific demethylase 1 (LSD1/KDM1A) inhibitor, was investigated herein to confirm its role in the progression of TNBC and reveal the potential mechanism. After treatment with ORY-1001 in MDA-MB-231 and BT549 cells, the cell proliferation and apoptosis were respectively measured by CCK-8 and TUNEL assays. The expression of proliferation- and apoptosis-associated proteins was tested by means of western blot analysis. Then, R1881, an androgen receptor (AR) agonist, was used to evaluate whether the effects of ORY-1001 on proliferation and apoptosis of TNBC cells was mediated by regulating AR. Results indicated that ORY-1001 treatment restrained the proliferation while enhanced the apoptosis of BC cells, accompanied by the change of proliferation- and apoptosis-related proteins expression. Furthermore, ORY-1001 reduced the level of AR in BC cells. After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY-1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY-1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY-1001 in the treatment of this disease.


Assuntos
Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Histona Desmetilases/farmacologia , Humanos , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
4.
Acta Histochem ; 124(2): 151856, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35077998

RESUMO

Neuroblastoma is a metastatic brain tumor particularly common in children. The cure rate is below 50% for patients of high-risk condition. Novel therapeutic agents and approaches are needed to improve the cure rate. Tumor necrosis factor-related and apoptosis-inducing ligand (TRAIL) is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells. Unfortunately, the common TRAIL resistance in cancers has hampered the clinical application of the ligand. Previously we prepared a novel TRAIL-armed ER derived nanosomal agent (ERN-T) that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins (IAPs), AZD5582. However, how AZD5582 sensitizes cancer cells to ERN-T remains not well understood. In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma, aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T. The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5Y when combined with AZD5582 whilst sparing normal cells. The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5Y but not in normal skin fibroblasts (NSFs). Importantly we discovered that TRAIL sensitization in SH-SY5Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP, MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5 (DR5) by the cotreatment of ERN-T and AZD5582. In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5Y xenograft neuroblastoma in nude mice. In conclusion, we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy, which is highly effective and safe for neuroblastoma.


Assuntos
Neuroblastoma , Ligante Indutor de Apoptose Relacionado a TNF , Alcinos , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oligopeptídeos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico
5.
Cell Biol Int ; 46(3): 336-343, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34941001

RESUMO

Osteosarcoma is a malignant tumor that often occurs in adolescents. There is an urgent need for new treatment options for osteosarcoma due to its poor prognosis after metastasis. Cancer stem cell (CSC) theory states that CSCs represent a small proportion of cancer cells. These CSC have self-renewal ability and are closely associated with cancer growth and metastasis as well as chemotherapy resistance. Similarly, osteosarcoma stem cells (OSCs) play an important role in the growth, metastasis, and chemotherapy resistance of osteosarcoma cells. Targeting OSCs may represent a future treatment of osteosarcoma. Furthermore, some genes have been shown to regulate the growth, metastasis, and chemotherapy resistance of osteosarcoma cells by altering the stemness of OSCs. Targeting these genes may help in the treatment of osteosarcoma. This review mainly discusses recent advances in the research of OSCs and their related genes.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Células-Tronco Neoplásicas/patologia , Osteossarcoma/patologia
6.
Nanotechnology ; 33(23)2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35193121

RESUMO

We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Células Endoteliais/patologia , Feminino , Glutationa , Humanos , Isoquinolinas , Nanopartículas/química , Fármacos Fotossensibilizantes , Porfirinas/química , Pirazóis , Pirimidinas
7.
Mol Pharm ; 19(2): 720-727, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34936367

RESUMO

Radiolabeled prostate-specific membrane antigen (PSMA) ligands have been rapidly adopted as part of patient care for prostate cancer. In this study, a new series of 18F-labeled PSMA-targeting agents was developed based on the high-affinity Glu-ureido-Lys scaffold and 18F-vinyl sulfones (VSs), the tumor uptake and tumor/major organ contrast of which could be tuned by pharmacokinetic linkers within the molecules. In particular, 18F-PEG3-VS-PSMAi showed the highest tumor uptake (12.1 ± 2.2%ID/g at 0.5 h p.i.) and 18F-PEG2-VS-PSMAi showed the highest tumor-to-liver ratio (T/L = 3.7 ± 1.0, 4.8 ± 1.2, and 6.3 ± 1.1 at 0.5, 1.5, and 3 h p.i. respectively). Significantly, compared with the FDA-approved 68Ga-PSMA-11, the newly developed 18F-PEG3-VS-PSMAi has an almost double tumor uptake (P < 0.0001) when tested in the same animal model. In conclusion, 18F-VS-labeled PSMA ligands are promising PET agents with prominent tumor uptake and high contrast. The lead agents 18F-PEG2-VS-PSMAi and 18F-PEG3-VS-PSMAi warrant further evaluation in prostate cancer patients.


Assuntos
Próstata , Neoplasias da Próstata , Animais , Antígenos de Superfície , Linhagem Celular Tumoral , Radioisótopos de Flúor/farmacocinética , Isótopos de Gálio , Radioisótopos de Gálio , Glutamato Carboxipeptidase II , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos/farmacocinética , Sulfonas
8.
Mol Cancer ; 21(1): 37, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35130920

RESUMO

PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células de Transição/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
9.
Clin. transl. oncol. (Print) ; 24(7): 1311-1321, julio 2022. graf
Artigo em Inglês | IBECS | ID: ibc-203830

RESUMO

PurposeOral squamous cell carcinoma (OSCC) is the most frequent type of oral cancer and is associated with high mortality. Membrane-associated ring-CH type finger 1 (MARCH1) is an E3 ubiquitin ligase with roles in immune regulation and cancer development. Whether MARCH1 has a specific role in OSCC, and if so through what mechanism, has not been explored.MethodsImmunohistochemistry was performed to examine MARCH1 expression in OSCC clinical samples and adjacent paracancerous tissues. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were conducted to determine mRNA expression and protein levels, respectively. Knockdown and overexpression experiments were carried out to evaluate the effects of MARCH1 on proliferation and apoptosis. To test protein–protein interaction, co-immunoprecipitation assay was performed. Finally, tumor cell grafting was utilized to test the function of MARCH in vivo.ResultsHigh MARCH1 expression in OSCC clinical samples correlated with poor patient prognosis. Functionally, MARCH1 knockdown in OSCC cells suppressed proliferation and promoted apoptosis, while MARCH1 overexpression displayed the opposite effects. We identified PH Domain And Leucine Rich Repeat Protein Phosphatase (PHLPP) 2 as an important target of MARCH1. Mechanistically, MARCH1 interacted with PHLPP2 and promoted PHLPP2 ubiquitination. Lastly, MARCH1 knockdown suppressed OSCC tumorigenicity in vivo and increased PHLPP2 protein level.


Assuntos
Humanos , Apoptose , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Neoplasias de Cabeça e Pescoço , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/patologia
10.
Clin. transl. oncol. (Print) ; 24(7): 1354-1364, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203834

RESUMO

BackgroundGastric cancer (GC) is a malignancy that belongs to one of the most common leading causes of cancer death. Cancer-associated fibroblasts (CAFs) promote the GC cells’ malignant behavior. It is still unknown how GC converts normal fibroblasts (NFs) to CAFs.MethodsGC cells were co-cultured with NFs. Bioinformatics was used to analyze the genes and signaling pathways that were changed in fibroblast. RT-PCR, western blot, and Elisa assays were used to detect the expression of cytokines in fibroblast and condition medium. Western blot and immunofluorescence demonstrated activation of relevant pathways in CAFs-like cells. Transwell, scrape, colony formation, and CCK-8 assays were performed to reveal the feedback effect of CAFs-like cells on GC cells.ResultsGC promoted the conversion of NFs to CAFs by secreting Interleukin 17A (IL-17). It included both morphological and molecular marker changes. This process was achieved by activating the nuclear factor-κB (NF-κB) pathway. On the other hand, CAFs cells could secrete C-X-C Motif Chemokine Ligand 8 (IL-8, IL-8), which promoted the malignant phenotype of GC cells. In this way, a feedback loop of mutual influence was constructed in the GC and tumor microenvironment (TME).ConclusionsOur research proved a novel model of GC-educated NFs. GC-IL-17-fibroblast-IL-8-GC axis might be a potential pathway of the interaction between GC and TME.


Assuntos
Humanos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Citocinas/metabolismo , Interleucina-17 , Interleucina-8 , Neoplasias Gástricas/patologia , Retroalimentação , Fibroblastos/metabolismo , Microambiente Tumoral
11.
Clin. transl. oncol. (Print) ; 24(7): 1395-1402, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203838

RESUMO

PurposeTumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer.MethodsA xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively).ResultsTumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion.ConclusionsActivity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.


Assuntos
Humanos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ácido Clodrônico/uso terapêutico , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Camundongos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico
12.
Clin. transl. oncol. (Print) ; 24(7): 1403-1412, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203839

RESUMO

PurposeThe role of autophagy in prostate cancer metastasis remains controversial, and the effects of the autophagy-related gene ATG5 on prostate cancer metastasis are poorly understood. This study aims to explore the effects of ATG5 on prostate cancer metastasis and its molecular mechanism.MethodsThe metastatic characteristics of LNCaP and DU145 cells were assessed by NOD/SCID mouse experiments, western blot, transwell assay, and wound-healing assay. Double membrane autophagic vesicle observation and the adenovirus-expressing mCherry-GFP-LC3B fusion protein were used to assess the autophagic characteristics of LNCaP and DU145 cells. The role of p62 in the accumulation of TWIST1 was confirmed by western blot under different conditions. The lentivirus particles of shATG5, NOD/SCID mice experiments, western blot, transwell assay, and wound-healing assay were used to confirm the role of ATG5 in TWIST1 accumulation and prostate cancer cell metastasis.ResultsWe identified a stabilizing effect of p62 on TWIST1 in the autophagic regulation of EMT and prostate cancer metastasis. The loss of ATG5 in DU145 cells resulted in autophagy deficiency and p62 accumulation, which stabilized TWIST1 and increased the TWIST1 level in prostate cancer cells, and eventually promoted EMT and metastasis. In comparison, LNCaP cells with regular ATG5 expression and autophagy status retained remarkable epithelial cell characteristics and had limited metastatic characteristics. Similar results were also found in wild-type LNCaP cells and LNCaP cells with stable ATG5 interference.ConclusionsOur research revealed ATG5-mediated autophagy as a key mechanism that controls the metastasis of prostate cancer by regulating p62 abundance and TWIST1 stabilization.


Assuntos
Humanos , Autofagia , Linhagem Celular Tumoral , Neoplasias Pulmonares , Neoplasias da Próstata/patologia , Proteínas Nucleares , Camundongos
13.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(3): 452-456, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35642154

RESUMO

Objective: To investigate the regulatory role of extracellular vesicles (EVs) carrying ATP binding cassette transporter G2 (ABCG2) on the drug resistance of lung adenocarcinoma cells and the relevant molecular mechanisms. Methods: A549 cells, human lung adenocarcinoma cells, were used to form cisplatin (or cis-Diaminedichloroplatinum, CDDP)-resistant lung adenocarcinoma cells, i.e., A549/CDDP cells. EVs from A549 and A549/CDDP cells were extracted by gradient centrifugation method and were hence named EVs 1 and EVs 2, respectively. The A549 cells were treated with EVs 1 and EVs 2 for 48 hours, and the cells were named A549-EVs 1 and A549-EVs 2 cells, respectively. A549/ ABCG2 cells were established by transfecting A549 cells with pCDNA3.1- ABCG2 recombinant plasmids. On the other hand, A549 cells transfected with empty vectors were named A549/pCDNA3.1 cells. MTT assay was conducted to calculate the 24-hour cell drug resistance index for CDDP. The ABCG2 gene expression in cells and EVs were assessed with real-time PCR. A549 and A549-EVs 2 cells were transplanted subcutaneously into nude mice, which were labeled the control group and the experimental group accordingly. After tumor formation, 3 mg/kg CDDP was intraperitoneally injected once a week for two times. The ABCG2 gene expression of subcutaneous transplanted tumor cells was examined by real-time PCR. The cell apoptosis rate of subcutaneous transplanted tumor cells was examined by flow cytometry. Results: Using the parental A549 cells as reference, the 24-h CDDP-resistance indexes of 549/CDDP, A549/ ABCG 2, A549/pCDNA3.1, A549-EVs 1, A549-EVs 2 cells were 7.17, 10.06, 1.02, 1.19 and 5.40, respectively. When comparing the ABCG2 gene expression levels in all cells and EVs, the findings were higher in A549/CDDP cells than those inA549 cells, higher in A549/ ABCG2 cells than those in A549/pCDNA3.1 or A549 cells, higher in EVs 2 than those in EVs 1, and higher in A549-EVs 2 than those in A549-EVs 1 cells ( P<0.01) . The volume of transplanted tumor and the ABCG2 gene expression level in the experimental group were higher than those in the control group, while the apoptosis rate was lower than that in the control group ( P<0.01). Conclusion: EVs carrying ABCG2 gene can regulate the drug resistance of lung adenocarcinoma cells.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Vesículas Extracelulares , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/genética , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus
14.
Pak J Pharm Sci ; 35(2): 605-612, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35642418

RESUMO

Fifteen novel 4-amino-quinolines (I1-III3) as antitumor agent were synthesized by p-nitroaniline and ethoxymethylene malonic ester (EMME) via condensation, cyclization, hydrolysis, decarboxylation, chlorination, nucleophilic substitution, reduction and amidation. The antitumor activity of compounds I1-III3 was evaluated on SGC-7901, BEL-7402 and A549 cancer cell lines. In vitro bioassay indicated that some compounds showed different degree activity against all tested cancer cell lines. Compound I1, I4 and II2 exhibited high effects against A549 cell lines (IC50 = 1.34µM, 1.36µM and 3.00µM, respectively). In addition, the result of molecular docking showed that compound I1, I4 and II2 could dock into the pocket of EGFR.


Assuntos
Antineoplásicos , Quinolinas , Células A549 , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Quinolinas/farmacologia , Uricosúricos
15.
Med Sci Monit Basic Res ; 28: e935139, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35642437

RESUMO

BACKGROUND Melanoma is one of the most aggressive types of cancer and it has shown a remarkable surge in incidence during the last 50 years. Melanoma has been projected to be continuously rising in the future. Therapy for advanced-type melanoma is still a challenge due to the low response rate and poor 10-year survival. Interestingly, several epidemiological and preclinical studies had reported that vitamin D deficiency was associated with disease progression in several cancer types. In vivo and in vitro studies revealed anti-proliferative, anti-angiogenic, apoptosis, and differentiation induction effects of calcitriol in various cancers. However, information on the effects of calcitriol (1,25(OH)2D3) on melanoma is still limited, and its mechanism remains unclear. MATERIAL AND METHODS In the present study, by utilizing B16-F10 cells, which is a melanoma cell line, we explored the anti-proliferative effect of calcitriol using cell viability assay, near-infrared imaging, expression of apoptosis-related genes using real-time polymerase chain reactions (PCR), and the expression of apoptosis proteins levels using western blot. In addition, we also assessed calcitriol uptake by B16-F10 cells using high-performance liquid chromatography (HPLC). RESULTS We found that calcitriol inhibits melanoma cell proliferation with an IC50 of 93.88 ppm (0.24 µM), as shown by cell viability assay. Additionally, we showed that B16-F10 cells are capable of calcitriol uptake, with a peak uptake time at 60 min after administration. Calcitriol was also able to induce apoptosis-related proteins such as caspase-3, caspase 8, and caspase-9. These effects of calcitriol reflect its potential utility as a potent adjuvant therapy for melanoma. CONCLUSIONS Calcitriol inhibits cell proliferation and induces apoptosis in B16-F10 cells.


Assuntos
Calcitriol , Melanoma Experimental , Animais , Apoptose , Calcitriol/farmacologia , Calcitriol/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo
16.
Drug Deliv ; 29(1): 1785-1799, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35642917

RESUMO

Retinoblastoma (Rb) represents 3% of all childhood malignancies and seriously endangers children's lives and quality of life. Early diagnosis and treatment can save children's vision as much as possible. Multifunctional nanoparticles have become a research hotspot in recent years and are expected to realize the integration of early diagnosis and early treatment. Therefore, we report a nanoparticle with dual-mode imaging, photothermal therapy, and immune activation: carbonized MOF nanoparticles (CM NPs) loaded with the immune polypeptide tuftsin (CMT NPs). The dual-mode imaging ability, antitumor effect, and macrophage immunity activation ability of these nanoparticles combined with laser irradiation were studied. The biosafety of CMT NPs was detected. The multifunctional magnetic nanoparticles enhanced photoacoustic (PA) and magnetic resonance (MR) imaging in vivo and in vitro, facilitating diagnosis and efficacy evaluation. The combined effect of CMT NPs and laser irradiation was recorded and verified. Through the accumulation of magnetic field nanoparticles in tumors, the photothermal conversion of nanoparticles under laser irradiation led directly to tumor apoptosis/necrosis, and the release of tuftsin induced macrophage M1-type activation, resulting in antitumor immune effects. Enhanced PA/MR imaging CMT NPs have great potential in dual-mode image-guided laser/immune cotherapy. The nanoparticles have high biosafety and have potential in cancer treatment.


Assuntos
Nanopartículas , Neoplasias da Retina , Retinoblastoma , Tuftsina , Linhagem Celular Tumoral , Criança , Humanos , Imunoterapia , Imagem Multimodal , Fototerapia , Qualidade de Vida , Retinoblastoma/terapia
17.
Microb Cell Fact ; 21(1): 98, 2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35643529

RESUMO

BACKGROUND: The fungal sesquiterpenes Illudin M and S are important base molecules for the development of new anticancer agents due to their strong activity against some resistant tumor cell lines. Due to nonspecific toxicity of the natural compounds, improvement of the pharmacophore is required. A semisynthetic derivative of illudin S (Irofulven) entered phase II clinical trials for the treatment of castration-resistant metastatic prostate cancer. Several semisynthetic illudin M derivatives showed increased in vitro selectivity and improved therapeutic index against certain tumor cell lines, encouraging further investigation. This requires a sustainable supply of the natural compound, which is produced by Basidiomycota of the genus Omphalotus. We aimed to develop a robust biotechnological process to deliver illudin M in quantities sufficient to support medicinal chemistry studies and future preclinical and clinical development. In this study, we report the initial steps towards this goal. RESULTS: After establishing analytical workflows, different culture media and commercially available Omphalotus strains were screened for the production of illudin M.Omphalotus nidiformis cultivated in a medium containing corn steep solids reached ~ 38 mg L-1 setting the starting point for optimization. Improved seed preparation in combination with a simplified medium (glucose 13.5 g L-1; corn steep solids 7.0 g L- 1; Dox broth modified 35 mL), reduced cultivation time and enhanced titers significantly (~ 400 mg L-1). Based on a reproducible cultivation method, a feeding strategy was developed considering potential biosynthetic bottlenecks. Acetate and glucose were fed at 96 h (8.0 g L-1) and 120 h (6.0 g L-1) respectively, which resulted in final illudin M titer of ~ 940 mg L-1 after eight days. This is a 25 fold increase compared to the initial titer. CONCLUSION: After strict standardization of seed-preparation and cultivation parameters, a combination of experimental design, empirical trials and additional supply of limiting biosynthetic precursors, led to a highly reproducible process in shake flasks with high titers of illudin M. These findings are the base for further work towards a scalable biotechnological process for a stable illudin M supply.


Assuntos
Glucose , Linhagem Celular Tumoral , Sesquiterpenos Policíclicos
18.
Cell Death Dis ; 13(5): 505, 2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35643812

RESUMO

The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Loss of XRCC2 compromises DNA damage repairs, and induced DNA damage burdens may increase the reliance on PARP-dependent DNA repairs of cancer cells to render cell susceptibility to PARP inhibitor therapy. Here we tested the hypothesis that XRCC2 loss sensitizes colorectal cancer (CRC) to PARP inhibitor in combination with radiotherapy (RT). We show that high levels of XRCC2 or PARP1 in LARC patients were significantly associated with poor overall survival (OS). Co-expression analyses found that low levels of PARP1 and XRCC2 were associated with better OS. Our in vitro experiments indicated that olaparib+IR led to reduced clonogenic survival, more DNA damage, and longer durations of cell cycle arrest and senescence in XRCC2-deficient cells relative to wild-type cells. Furthermore, our mouse xenograft experiments indicated that RT + olaparib had greater anti-tumor effects and led to long-term remission in mice with XRCC2-deficient tumors. These findings suggest that XRCC2-deficient CRC acquires high sensitivity to PARP inhibition after IR treatment and supports the clinical development for the use of olaparib as a radiosensitizer for treatment of XRCC2-deficient CRC.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/radioterapia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/uso terapêutico , Humanos , Camundongos , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
19.
J Cancer Res Ther ; 18(2): 362-369, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35645101

RESUMO

Aim: This study aimed to explore the role of pantoprazole (PPZ) in affecting the sensitivity of cervical cancer (CC) cells to cisplatin. Methods: HeLa and CaSki cells were exposed to cisplatin and/or PPZ treatment. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, flow cytometry, wound healing, and transwell assays were performed to detect cell viability, proliferation, apoptosis, migration, and invasion of CC cells, respectively. Then, expressions of Beclin-1, LC3, and p62 were measured by western blot. Rapamycin (Rapa), acting as an autophagy activator, was applied to confirm the effect of autophagy on the sensitivity of CC cells to cisplatin. Results: Cisplatin treatment suppressed cell viability and proliferation and accelerated apoptosis of CC cells. Combination of cisplatin and PPZ or PPZ alone significantly inhibited cell viability, proliferation, migration, and invasion, and increased cell apoptosis of CC cells. Cisplatin enhanced expression levels of Beclin1 and LC3II/I, and reduced p62 expression. Combination of cisplatin and PPZ significantly decreased the expression levels of Beclin1 and LC3II/I, but increased p62 expression. The autophagy activator, Rapa, eliminated the inhibitory effects of the combination of cisplatin and PPZ on autophagy, and enhanced cell viability, but inhibited apoptosis of CC cells. Conclusion: PPZ promotes the sensitivity of CC cells to cisplatin by inhibiting cisplatin-induced cell autophagy.


Assuntos
Antineoplásicos , Neoplasias do Colo do Útero , Antineoplásicos/farmacologia , Autofagia , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Humanos , Pantoprazol/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico
20.
Biomed Res Int ; 2022: 9912776, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35647179

RESUMO

Objective: To study the mechanism of curcumol affecting the proliferation and apoptosis of liver cancer cells through the DJ-1/PTEN/PI3K/AKT pathway. Method: HepG2 cells were cultured in vitro, treated with curcumol at concentrations of 10, 30, and 100 µg/mL, and DMSO was used as a control. The levels of cell proliferation and apoptosis were measured by CCK-8 and flow cytometry, respectively. RT-PCR and western blot were used to detect PTEN, p-AKT, DJ-1, and PI3K gene and protein expression changes. Result: (1) Compared with the DMSO blank control group, the proliferation level of liver cancer cells in the 10 µg/mL curcumol group decreased, and the proportion of apoptosis increased (p <0.05). (2) Compared with the blank control group and the 10 and 30 µg/mL concentration groups, the proliferation level of liver cancer cells in the 100 µg/mL curcumol group was significantly reduced, and the proportion of cell apoptosis was significantly increased (p < 0.05). (3) Curcumol can significantly increase the expression of PTEN gene and protein in liver cancer cells and reduce the expression of DJ-1 and PI3K genes and protein in liver cancer cells (p < 0.05). Conclusion: Curcumol can regulate DJ-1, PTEN, PI3K, and AKT signal transduction pathways, inhibit cell proliferation, and cause a significant increase in the proportion of cell apoptosis, and the pharmacodynamic effect of curcumol is dependent on the time and dose of action.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Dimetil Sulfóxido/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...