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1.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342264

RESUMO

Colorectal cancer (CRC) remains a leading cause of cancer death, and its mortality is associated with metastasis and chemoresistance. We demonstrate that oxaliplatin-resistant CRC cells are sensitized to TRAIL-mediated apoptosis. Oxaliplatin-resistant cells exhibited transcriptional downregulation of caspase-10, but this had minimal effects on TRAIL sensitivity following CRISPR-Cas9 deletion of caspase-10 in parental cells. Sensitization effects in oxaliplatin-resistant cells were found to be a result of increased DR4, as well as significantly enhanced DR4 palmitoylation and translocation into lipid rafts. Raft perturbation via nystatin and resveratrol significantly altered DR4/raft colocalization and TRAIL sensitivity. Blood samples from metastatic CRC patients were treated with TRAIL liposomes, and a 57% reduction of viable circulating tumor cells (CTCs) was observed. Increased DR4/lipid raft colocalization in CTCs was found to correspond with increased oxaliplatin resistance and increased efficacy of TRAIL liposomes. To our knowledge, this is the first study to investigate the role of lipid rafts in primary CTCs.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/fisiopatologia , Resistencia a Medicamentos Antineoplásicos/genética , Oxaliplatina/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Microdomínios da Membrana/metabolismo , Pessoa de Meia-Idade , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Regulação para Cima
2.
J Transl Med ; 19(1): 280, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193174

RESUMO

BACKGROUND: Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown. METHODS: The expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot. RESULTS: We found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p < 0.001). SRPK1 overexpression enhanced the anti-apoptosis ability of colon cancer cells, whereas SRPK1 silencing had the opposite effect under oxaliplatin treatment. Mechanistically, SRPK1 enhances IKK kinase and IκB phosphorylation to promote NF-κB nuclear translocation to confer oxaliplatin resistance. CONCLUSIONS: Our findings suggest that SRPK1 participates in colon cancer progression and enhances the anti-apoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and thus might be a potential pharmaceutically target for colon cancer treatment.


Assuntos
Neoplasias do Colo , NF-kappa B , Apoptose , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Humanos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt
3.
Adv Clin Exp Med ; 30(8): 831-838, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34286514

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most severe malignant cancers that leads to high death rate worldwide. Recent research revealed that long non-coding RNAs (lncRNAs) exert a critical role regarding chemoresistance in numerous cancers, including HCC. OBJECTIVES: Our research aimed to explore the function and molecular mechanism of lncRNA PCGEM1 on oxaliplatin resistance of HCC in vitro. MATERIAL AND METHODS: Expression of the lncRNA PCGEM1, together with miR-129-5p, and the mRNA level of ETV1 and drug resistance-related genes including LRPA, MDR1 and MDR3 were determined using quantitative real-time polymerase chain reaction (qRT-PCR) in an oxaliplatin-resistant HCC cell line (Hep3B/OXA). Cell Counting Kit-8 (CCK-8) was employed to assess the viability and cell survival rate, and transwell assays were performed to measure the number of migrated or invaded cells. In addition, the relation among lncRNA PCGEM1, miR-129-5p and ETV1 were determined using luciferase assay. RESULTS: Our data indicated that PCGEM1 and ETV1 expression were enhanced in Hep3B/OXA cells. Furthermore, knockdown of lncRNA PCGEM1 significantly decreased the migration, invasion and mRNA expressions of LRPA, MDR1 and MDR3, and the cell viability in Hep3B/OXA cells. The starBase online tool and luciferase assays verified that miR-129-5p targeted PCGEM1 and ETV1, signifying that PCGEM1 could enhance ETV1 expression via suppressing miR-129-5p. CONCLUSIONS: Our findings demonstrated that PCGEM1 modulated oxaliplatin resistance by targeting the miR-129-5p/ETV1 pathway in HCC in vitro, suggesting a potential strategy for the treatment of chemoresistant HCC.


Assuntos
Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , MicroRNAs/genética , Oxaliplatina/farmacologia , RNA Longo não Codificante/genética , Fatores de Transcrição
4.
Nat Commun ; 12(1): 4310, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262026

RESUMO

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Macrófagos/transplante , Fotoquimioterapia/métodos , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Portadores de Fármacos/química , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Indóis/administração & dosagem , Indóis/química , Indóis/farmacologia , Raios Infravermelhos , Macrófagos/química , Nanomedicina , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxaliplatina/administração & dosagem , Oxaliplatina/química , Oxaliplatina/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia
5.
Nanoscale ; 13(24): 10906-10915, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34128036

RESUMO

Cancer vaccines are made from tumor-specific antigens, which are then injected back into the body to activate immune responses for cancer immunotherapy. Despite the high specificity and therapeutic efficiency, the vaccine has huge challenges such as complex preparation process, expensiveness and limited durational effects. Herein, a strategy to develop in situ cancer vaccines by enhancing the immunomodulatory effects for immunogenic cell death (ICD) is presented. First, amorphous iron oxide-packaged oxaliplatin (AIOoxp) nanoprodrugs with a high drug loading efficiency of 12.9% were prepared. By utilizing tumor microenvironment (TME) as an endogenous stimulus, this inorganic nanoprodrug can effectively realize TME-responsive combined treatments of chemotherapy and chemodynamic therapy (CDT), and thus achieve dual and precise ICD induction. Further, in vivo immunopotentiation performances further prove that this enhanced ICD effect is able to efficiently promote the maturity of dendritic cells (DCs), T cell activation and correlative cytokine secretion. Furthermore, the obtained nanoprodrugs not only reduce systemic toxicities of Oxp and achieve T1/T2 magnetic resonance imaging (MRI), but also dramatically inhibit tumor growth and lung metastasis. We believe that the design of in situ cancer vaccines by enhancing the ICD effects will inspire future studies on cancer vaccines.


Assuntos
Vacinas Anticâncer , Neoplasias , Linhagem Celular Tumoral , Morte Celular Imunogênica , Imunoterapia , Oxaliplatina/farmacologia , Microambiente Tumoral
6.
Eur J Med Chem ; 223: 113650, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34174741

RESUMO

Panx-1 is a membrane channel protein involved in some pathologies such as ischemic stroke, cancer and neuropathic pain, thus representing a promising therapeutic target. We present here a study aimed at obtaining the first class of selective Panx-1 blockers, a new topic for pharmaceutical chemistry, since all compounds used so far for the study of this channel have different primary targets. Among various scaffolds analyzed, the indole nucleous emerged, whose elaboration yielded interesting Panx-1 blockers, such as the potent 5-sulfamoyl derivatives 14c and 15b (I% = 100 at 50 µM). In vivo tests performed in the mouse model of oxaliplatin-induced neuropathy, demonstrated that the hypersensitivity was completely reverted by treatment with 15b (1 nmol, administered intrathecally), suggesting a relationship between this effect and the channel blocking ability. Finally, we decided to perform a virtual screening study on compounds 5b, 6l and 14c using a recently resolved cryo-EM structure of hPanx-1 channel, to try to relate the potency of our new inhibitors.


Assuntos
Desenho de Fármacos , Indóis/química , Proteínas do Tecido Nervoso/metabolismo , Animais , Sítios de Ligação , Conexinas/antagonistas & inibidores , Conexinas/metabolismo , Modelos Animais de Doenças , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Oxaliplatina/farmacologia , Relação Estrutura-Atividade
7.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065887

RESUMO

Drosophila melanogaster (Drosophila) models of cancer are emerging as powerful tools to investigate the basic mechanisms underlying tumour progression and identify novel therapeutics. Rapid and inexpensive, it is possible to carry out genetic and drug screens at a far larger scale than in vertebrate organisms. Such whole-organism-based drug screens permits assessment of drug absorption and toxicity, reducing the possibility of false positives. Activating mutations in the Wnt and Ras signalling pathways are common in many epithelial cancers, and when driven in the adult Drosophila midgut, it induces aggressive intestinal tumour-like outgrowths that recapitulate many aspects of human colorectal cancer (CRC). Here we have taken a Drosophila CRC model in which tumourous cells are marked with both GFP and luciferase reporter genes, and developed novel high-throughput assays for quantifying tumour burden. Leveraging these assays, we find that the Drosophila CRC model responds rapidly to treatment with standard CRC-drugs, opening the door to future rapid genetic and drug screens.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Genes Reporter , Animais , Animais Geneticamente Modificados , Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Drosophila melanogaster , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Luciferases/genética , Luciferases/metabolismo , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Mol Sci ; 22(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065633

RESUMO

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial-mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial-mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Neoplasias do Colo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Antígenos CD/metabolismo , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Bases de Dados Genéticas , Molécula de Adesão da Célula Epitelial/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Técnicas de Silenciamento de Genes , Humanos , Queratina-20/metabolismo , Invasividade Neoplásica/genética , Oxaliplatina/farmacologia , Transporte Proteico , Vimentina/metabolismo , beta Catenina/metabolismo
9.
Muscle Nerve ; 64(2): 225-234, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34036599

RESUMO

INTRODUCTION/AIMS: Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention could improve these adverse conditions. METHODS: Mice were chronically treated with oxaliplatin alone or in conjunction with exercise. Behavioral studies, including mechanical allodynia, rotarod, open-field, and grip-strength tests, were performed. After euthanasia, multiple organs and four different muscle types were dissected and weighed. The cross-sectional area (CSA) of muscle fibers in the gastrocnemius muscle was assessed and gene expression analysis performed on the forelimb triceps muscle. RESULTS: Oxaliplatin-treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behavior deficits that were not significantly improved by exercise. Oxaliplatin-treated exercised mice showed modest evidence of reduced muscle wastage compared with mice treated with oxaliplatin alone, and exercised mice demonstrated evidence of a mild increase in CSA of muscle fibers. DISCUSSION: Exercise intervention did not improve signs of peripheral neuropathy but moderately reduced the negative impact of oxaliplatin chemotherapy related to muscle morphology, suggesting the potential for exploring the impact of exercise on reducing oxaliplatin-induced neuromuscular toxicity in cancer patients.


Assuntos
Hiperalgesia/terapia , Doenças do Sistema Nervoso Periférico/terapia , Condicionamento Físico Animal/fisiologia , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Masculino , Camundongos Endogâmicos C57BL , Oxaliplatina/farmacologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente
10.
Mol Med Rep ; 24(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33982772

RESUMO

Liver cancer remains one of the leading causes of cancer deaths worldwide. The therapeutic effect of oxaliplatin on liver cancer is often limited by acquired resistance of the cancer cells. Abnormal activation of the PI3K/AKT pathway plays an important role in the acquired resistance of oxaliplatin. The present study investigated the effects of the PI3K inhibitor LY­294002 and AKT inhibitor MK2206 on the chemosensitivity of oxaliplatin­resistant liver cancer cells and the molecular mechanism involved. An oxaliplatin­resistant liver cancer cell line HepG2R was developed. MTT assay, clone formation experiments, flow cytometry and Annexin V­FITC/PI staining were used to determine the proliferation, cycle and apoptosis of HepG2R cells when oxaliplatin was combined with LY­294002 or MK2206 treatment. The effects of LY­294002 and MK­2206 on the abnormal activation of PI3K/AKT pathway and hypoxia inducible factor (HIF)­1α protein level in HepG2R cells were detected using western blotting. The results indicated that the PI3K/AKT pathway is stably activated in HepG2R cells. Compared with the AKT inhibitor MK2206, the PI3K inhibitor LY­294002 more effectively downregulated the phosphorylation levels of p85, p110α, p110ß, p110γ and AKT in the PI3K/AKT pathway in HepG2R cells, and more effectively inhibited the proliferation of the cells. LY­294002 enhanced the chemotherapy sensitivity of HepG2R cells to oxaliplatin by inducing G0/G1 phase arrest and increasing the proportion of apoptotic cells. In addition, LY­294002 reduced the level of HIF­1α, which is highly expressed in HepG2R cells. It was concluded that LY­294002 enhanced the chemosensitivity of liver cancer cells to oxaliplatin by inhibiting the PI3K/AKT signaling pathway, which may be related to the inhibition of HIF­1α expression. These findings may have clinical significance for the treatment of oxaliplatin­resistant liver cancer.


Assuntos
Antineoplásicos/farmacologia , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Morfolinas/farmacologia , Oxaliplatina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Células Hep G2 , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores
11.
Cell Death Dis ; 12(5): 463, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33966039

RESUMO

Resistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Oxaliplatina/uso terapêutico , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antineoplásicos/farmacologia , Neoplasias Colorretais/genética , Humanos , Oxaliplatina/farmacologia
12.
Cell Death Dis ; 12(5): 485, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986248

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in colorectal cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin-resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL's role in conferring resistance to oxaliplatin-induced apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Oxaliplatina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Humanos , Camundongos , Camundongos Nus , Oxaliplatina/farmacologia , Prognóstico , Transfecção
13.
Cell Death Dis ; 12(6): 519, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021129

RESUMO

UPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 in oxaliplatin resistance in colorectal cancer (CRC) remains unknown. In our study, UPF1 is upregulated in CRC in mRNA and protein levels and overexpression of UPF1 predicts a poor overall survival (OS) and recurrence-free survival (RFS) in CRC patients and is an independent risk factor for recurrence. UPF1 promotes chemoresistance to oxaliplatin in vitro and in vivo. UPF1-induced oxaliplatin resistance can be associated with interaction between zinc finger of UPF1 and Toprim of TOP2A and increasing phosphorylated TOP2A in a SMG1-dependent manner. Moreover, UPF1 maintains stemness in a TOP2A-dependent manner in CRC. Taken together, UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced chemoresistance to oxaliplatin in CRC, which may result from regulation of TOP2A activity and maintenance of stemness. Our findings could provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.


Assuntos
Neoplasias Colorretais/genética , DNA Topoisomerases Tipo II/metabolismo , Oncogenes/genética , Oxaliplatina/uso terapêutico , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Transativadores/metabolismo , Neoplasias Colorretais/patologia , Humanos , Pessoa de Meia-Idade , Oxaliplatina/farmacologia
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(4): 504-513, 2021 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-33963708

RESUMO

OBJECTIVE: To explore the synergistic inhibitory effect of polysaccharide from Trichoderma pseudokoningii (EPS) and oxaliplatin (Oxa) on colorectal cancer (CRC) HCT116 cells. OBJECTIVE: HCT116 cells were treated with 8 µg/mL Oxa and 100 µg/mL EPS alone or in combination, and the changes in cell viability was assessed with CCK-8 assay. CompuSyn software was used for fitting the Fa-CI curve to evaluate the combined effect of the two agents. Flow cytometry was performed to analyze cell apoptosis and cell cycle changes, and wound healing assay and Transwell assay were used to examine the migration ability of the treated cells. Oxa- and EPS-related genes and CRC-related genes were intersected for protein-protein interaction (PPI) analysis and GO and KEGG enrichment analyses. OBJECTIVE: Treatment with Oxa alone or in combination with EPS significantly inhibited the viability of HCT116 cells in a dose- and time-dependent manner, and the two agents exhibited a significant synergistic effect (CI < 1). The combined treatment with Oxa and EPS resulted in a significantly higher total cell apoptosis rate and a higher percentage of cells in S phase than Oxa alone and the control treatment (P < 0.05). EPS and Oxa alone both inhibited the migration of HCT116 cells, and their combination produced a stronger inhibitory effect. GO enrichment analysis of the key genes related with Oxa, EPS and CRC suggested that these genes were involved mainly in such biological processes as exogenous apoptosis signaling, cell response to chemical stress, and reactive oxygen metabolism; KEGG analysis showed that these genes were involved in the pathways of drug resistance, apoptosis and angiogenesis. OBJECTIVE: EPS and Oxa can synergistically inhibit the proliferation of HCT116 cells possibly through the PI3K-Akt, MAPK, VEGF, and p53 signaling pathways.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Trichoderma , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Neoplasias Colorretais/tratamento farmacológico , Células HCT116 , Humanos , Hypocreales , Compostos Organoplatínicos/farmacologia , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Fosfatidilinositol 3-Quinases , Polissacarídeos/farmacologia
15.
Can J Gastroenterol Hepatol ; 2021: 8870907, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33824865

RESUMO

Background: Oxaliplatin is the first-choice chemotherapy method for patients with advanced colon cancer. However, its resistance leads to treatment failure for many patients. In our experiments, we aim to elucidate the associations among TRIM29 protein, mutant P53, and the resistance of colon cancer cells to oxaliplatin. Methods: HCT116 and HT-29 cells were cultured and transfected with plasmids pIRES2-ZsGreen1-TRIM29-flag. Western blot and real-time qRT-PCR were utilized to examine the protein and mRNA expressions of TRIM29 and other related markers, respectively. MTT assay was utilized to determine the cell growth rate and generate the inhibition curve. Continuous culture in low-concentration oxaliplatin was conducted to construct oxaliplatin-resistant cell lines. The coimmunoprecipitation method and immunofluorescence detection were used to examine the interaction between TRIM29 and mutant P53 protein in HT29 cells. Results: We successfully transfected pIRES2-ZsGreen1-TRIM29-flag into HCT116 and HT29 cells, which were utilized in the whole experiments. TRIM29 significantly increased the sensitivity of P53 mutant colon cancer cell HT29 to oxaliplatin. The oxaliplatin-resistant model of P53 mutant colon cancer cell HT29 was successfully constructed. TRIM29 physically bound with mutant P53 and retained it in the cytoplasm from the nucleus, which inhibited its transcription function of downstream genes such as MDR1. In addition, TRIM29 successfully reversed the resistance of HT29-OX resistant cell model to oxaliplatin. Conclusion: In mutant P53 colon cancer cell HT29, TRIM29 greatly increased the sensitivity of HT29 to oxaliplatin and reverse oxaliplatin resistance. The underlying mechanism is TRIM29 may increase the sensitivity of HT29 to oxaliplatin by blocking the transcriptional function of mutant P53, which inhibits the transcription function of its downstream gene such as MDR1.


Assuntos
Neoplasias do Colo , Proteína Supressora de Tumor p53 , Apoptose , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Compostos Organoplatínicos/farmacologia , Oxaliplatina/farmacologia , Fatores de Transcrição , Proteína Supressora de Tumor p53/genética
16.
Aging (Albany NY) ; 13(10): 13515-13534, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33819186

RESUMO

Oxaliplatin resistance can develop in colorectal cancer (CRC), which may involve inhibition of ferroptosis, although further research is needed to understand this potential mechanism. We evaluated CRC cells with acquired oxaliplatin resistance (HCT116-Or) or congenital resistance (H716) to determine whether a ferroptosis inducer (RSL3) or inhibitor (liproxstatin-1) could modulate the effects of oxaliplatin. The results suggested that induction of ferroptosis could significantly reverse the oxaliplatin resistance of the CRC cells. Bioinformatic and cytobiological searches also revealed that KIF20A was highly expressed in the oxaliplatin-resistant cell lines and was strongly correlated with survival among CRC patients. Silencing KIF20A enhanced cellular sensitivity to oxaliplatin both in vivo and in vitro, and silencing KIF20A also suppressed NUAK1 activation, while a NUAK1 agonist (ETC-1002) could reverse the oxaliplatin sensitivity of KIF20A-silenced cells. Moreover, silencing NUAK1 up-regulated the expression of PP1ß, down-regulated the phosphorylation of downstream GSK3ßSer9, suppressed the nuclear import of Nrf2, inhibited the expression of a ferroptosis key negative regulatory protein (GPX4), and blocked cellular resistance. Applying a Nrf2 agonist (oltipraz) also reversed the oxaliplatin sensitivity of NUAK1-silenced cells. Therefore, cellular ferroptosis may be inhibited via the KIF20A/NUAK1/PP1ß/GPX4 pathway in CRC cells, which may underly the resistance of CRC to oxaliplatin.


Assuntos
Neoplasias Colorretais/patologia , Ferroptose , Cinesina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxaliplatina/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Proteínas Quinases/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Ferroptose/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Camundongos Nus , Camundongos SCID , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/genética
17.
BMC Cancer ; 21(1): 354, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794823

RESUMO

BACKGROUND: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. METHODS: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). CONCLUSIONS: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.


Assuntos
Biomarcadores Tumorais/metabolismo , Capecitabina/uso terapêutico , Fluoruracila/uso terapêutico , Oxaliplatina/uso terapêutico , Idoso , Capecitabina/farmacologia , Feminino , Fluoruracila/farmacologia , Humanos , Masculino , Metástase Neoplásica , Oxaliplatina/farmacologia , Estudos Prospectivos
18.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920318

RESUMO

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0-4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15-20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.


Assuntos
Fator 2 Relacionado a NF-E2/genética , Oxaliplatina/farmacologia , Oxazóis/farmacologia , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Humanos , Camundongos , NF-kappa B/genética , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Oxaliplatina/efeitos adversos , Dor/induzido quimicamente , Dor/genética , Dor/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos
19.
Acta Biochim Biophys Sin (Shanghai) ; 53(5): 584-592, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33772548

RESUMO

Oxaliplatin (OXA) resistance limits the efficiency of treatment for hepatocellular carcinoma (HCC). Studies have shown that the PDZ-binding kinase (PBK) plays important roles in tumors. However, the role of PBK in HCC is still a problem. In this study, we explored whether PBK is involved in the chemoresistance to OXA in HCC. Expressions of PBK in six HCC cell lines and one human hepatocytes line were determined by real-time quantitative PCR and western blot analysis. SNU-182 and HepG2 cells were chosen to induce OXA resistance. PBK was silenced or overexpressed in OXA-resistant and sensitive cell lines. Then, cell proliferation, migration, and invasion were measured by cholecystokinin-8 assay and Transwell assay, respectively. The Cancer Genome Atlas dataset showed that PBK is highly expressed in HCC and signifies poor prognosis to patient with HCC. Results showed that expression of PBK in HCC cells was significantly higher than that in THLE2 cells, and it was further increased in OXA-resistant HCC cells. Silencing of PBK promoted the sensitivity of drug-resistant HCC cells to OXA. Overexpression of PBK relieved the apoptosis induced by OXA and promoted the migration and invasion of OXA-sensitive HCC cells. Thus, this study revealed that high PBK expression is correlated with OXA resistance in HCC cells, which may provide a promising therapeutic target for treating HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Oxaliplatina/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , PTEN Fosfo-Hidrolase/genética
20.
Theranostics ; 11(10): 4672-4687, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754020

RESUMO

Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin.


Assuntos
Catepsinas/genética , Neurônios/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Catepsinas/antagonistas & inibidores , Catepsinas/efeitos dos fármacos , Quimioterapia Adjuvante , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos , Feminino , Fluoruracila/uso terapêutico , Gânglios Espinais , Humanos , Técnicas In Vitro , Leucovorina/uso terapêutico , Masculino , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Terapia de Alvo Molecular , Condução Nervosa , Neurônios/efeitos dos fármacos , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/efeitos adversos , Oxaliplatina/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos Prospectivos
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