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PURPOSE: Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells. METHODS: Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2. RESULTS: Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells. CONCLUSION: Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.
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Curcumina , Glicoproteínas , Neoplasias Pancreáticas , Humanos , Curcumina/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Mensageiro , Proliferação de CélulasRESUMO
Mediated electron transfer (MET) is fundamental to many biological functions, including cellular respiration, photosynthesis, and enzymatic catalysis. However, leveraging the MET process to enable the release of therapeutic gases has been largely unexplored. Herein, we report the bio-inspired activation of a series of UV-absorbing N-nitrosamide derivatives (NOA) under red light exposure, enabling the quantitative release of nitric oxide (NO) gasotransmitter via an MET process. The cornerstone of our design is the covalent linkage of a 2,4-dinitroaniline moiety, which acts as an electron mediator to the N-nitrosamide groups. This facilitates efficient electron transfer from the excited palladium(II) meso-tetraphenyltetrabenzoporphyrin (PdTPTBP) photocatalyst and the selective activation of NOA. Our approach has been validated with distinct photocatalysts and various N-nitrosamides, including those derived from carbamates, amides, and ureas. Notably, the modulation of the linker length between the electron mediator and N-nitrosamide groups serves as a regulatory mechanism for controlling NO release kinetics. Moreover, this biomimetic NO release platform demonstrates effective operation under both normoxic and hypoxic conditions, and it enables localized delivery of NO under physiological conditions, exhibiting significant anticancer efficacy within the phototherapeutic window and enhanced selectivity towards tumor cells.
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BACKGROUND & AIMS: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown. METHODS: We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment. RESULTS: We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1+ macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligandâreceptor networks among malignant cells, SPP1+ macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1+ macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration. CONCLUSIONS: We identified that the TIB structure formed by the interaction of SPP1+ macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC. IMPACT AND IMPLICATIONS: Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Microambiente Tumoral , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodosRESUMO
INTRODUCTION: Hepatocellular carcinoma located in hepatic segment VI/VII or close to the adrenal gland were generally considered challenging for minimally invasive resection. For these individualized patients, this may be overcome by the novel use of a retroperitoneal laparoscopic hepatectomy; however, minimally invasive retroperitoneal liver resection is difficult to perform.1-3 This video article demonstrates a pure retroperitoneal laparoscopic hepatectomy for a subcapsular hepatocellular carcinoma. VIDEO: A 47-year-old male patient with Child-Pugh A liver cirrhosis presented with a small tumor located very close to the adrenal gland next to segment VI of the liver. An enhanced abdominal computed tomographic scan demonstrated a solitary 2.3 × 1.6 cm lesion. Considering the special location of the lesion, a pure retroperitoneal laparoscopic hepatectomy was performed after obtaining the patient's consent. The patient was positioned in the flank position. The procedure was carried out using the balloon technique for a retroperitoneoscopic approach, with the patient in the lateral kidney position. The retroperitoneal space was first accessed through a 12-mm skin incision above the anterior superior iliac spine in the mid-axillary line and was expanded by inflating a glove balloon to 900 mL. A 5 mm port below the 12th rib in the posterior axillary line and a 12 mm port below the 12th rib in the anterior axillary line were placed. Following incision of Gerota's fascia, the dissection plane between the perirenal fat and the anterior renal fascia located at the superomedial side of the kidney was explored. The retroperitoneum behind the liver was fully exposed after the upper pole of the kidney was isolated. After localization of the tumor by intraoperative ultrasonography through the retroperitoneum, the retroperitoneum was dissected directly above the tumor. We used an ultrasonic scalpel to divide the hepatic parenchyma, and a Biclamp for hemostasis. The blood vessel was clamped using titanic clips, and the specimen was extracted using a retrieval bag following resection. A drainage tube was placed after completing meticulous hemostasis. Closure of the retroperitoneum was performed using a conventional suture method. RESULTS: The total operation time was 249 min, with an estimated blood loss of 30 mL. The final histopathological diagnosis showed a 3.0 × 2.2 × 2.0 cm-sized hepatocellular carcinoma. The patient was discharged on postoperative day 6 without any complications. CONCLUSION: Lesions located in segment VI/VII or close to the adrenal gland were generally considered difficult for minimally invasive resection. Under these circumstances, a retroperitoneal laparoscopic hepatectomy might be a more suitable option as it is a safe, effective and complementary approach to standard minimally invasive technology for the resection of small hepatic tumors in these special locations of the liver.
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Carcinoma Hepatocelular , Laparoscopia , Neoplasias Hepáticas , Masculino , Humanos , Pessoa de Meia-Idade , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Espaço Retroperitoneal/cirurgia , Hepatectomia/métodos , Laparoscopia/métodosRESUMO
A novel NIR-II small-molecule D-A type organic fluorophore conjugation of triphenylamine, thiophene, and benzo[c,d] indol groups (TPA-Et) with strong electron-donating and accepting groups has been synthesized. The dye shows a significant Stokes shift for efficient fluorescence in the NIR-II region and high photothermal performance. The TPA-Et was then encapsulated by an amphiphilic copolymer P(OEGMA)20-P(Asp)14, and micelles (P@TP) has been prepared with outstanding NIR-II imaging performance, excellent photothermal conversion efficiency (52.5%) under 808 nm laser irradiation, and good photostability. Fluorescence imaging experiments have consistently shown that P@TP can image tiny blood vessels in mice, enrich effectively in the tumor region, and maintain a relatively stable NIR-II fluorescence signal in the tumor area for a long time up to 60 h. In vivo photothermal therapy has a highly significant anticancer effect without tumor recurrence, demonstrating the apparent advantages of P@TP as a NIR nanotheranostic platform in NIR-II imaging-guided photothermal therapy.
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Nanopartículas , Neoplasias , Animais , Elétrons , Corantes Fluorescentes/química , Camundongos , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Peptídeos , Fototerapia , Nanomedicina Teranóstica/métodosRESUMO
BACKGROUND & AIMS: Pyogenic liver abscesses (PLA) are space-occupying lesions in the liver that produce high morbidity and mortality. The clinical characteristics and prognosis of abscesses is different depending on the bacterial culture results and require different strategies for management. The aim of this study was to investigate the clinical characteristics and prognostic factors of patients with PLA. METHODS: Clinical features, laboratory tests and etiology of PLA between 2006 to 2011 and 2012 to 2017 in a single hospital were retrospectively reviewed. The incidence and mortality of PLA caused by Escherichia coli and Klebsiella pneumoniae were compared and the risk factors for multiple organ dysfunction (MODS) and endophthalmitis were evaluated. RESULTS: Among the 1,572 PLA patients, the proportion with PLA increased from 333 (21.2%) in 2006-2011 to 1,239 (78.8%) in 2012-2017 without any investigation and treatment procedure differences. K pneumoniae was the main isolate in analysed pus cultures (85.6%). The mortality rate of patients with K pneumoniae infection was lower in the latter period (6.7% vs 0.7%, P = .035). Multivariate analyses revealed that age, fever, MODS and length of hospital stay were factors affecting poor prognosis (death + unhealed/uncured) in PLA patients after treatment and that cardiovascular disease, pleural effusion and pulmonary infection were risk factors for MODS, while diabetes mellitus was the only risk factor for endophthalmitis. Most patients (95.5%) with PLA recovered after abscess drainage/puncture and antibiotic therapy. CONCLUSIONS: Pleural effusion, fever, MODS and length of hospital stays were factors useful in predicting PLA outcomes.
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Abscesso Hepático Piogênico , Antibacterianos/uso terapêutico , Escherichia coli , Humanos , Klebsiella pneumoniae , Abscesso Hepático Piogênico/diagnóstico , Abscesso Hepático Piogênico/epidemiologia , Abscesso Hepático Piogênico/terapia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Most existing algorithms have been focused on the segmentation from several public Liver CT datasets scanned regularly (no pneumoperitoneum and horizontal supine position). This study primarily segmented datasets with unconventional liver shapes and intensities deduced by contrast phases, irregular scanning conditions, different scanning objects of pigs and patients with large pathological tumors, which formed the multiple heterogeneity of datasets used in this study. METHODS: The multiple heterogeneous datasets used in this paper includes: (1) One public contrast-enhanced CT dataset and one public non-contrast CT dataset; (2) A contrast-enhanced dataset that has abnormal liver shape with very long left liver lobes and large-sized liver tumors with abnormal presets deduced by microvascular invasion; (3) One artificial pneumoperitoneum dataset under the pneumoperitoneum and three scanning profiles (horizontal/left/right recumbent position); (4) Two porcine datasets of Bama type and domestic type that contains pneumoperitoneum cases but with large anatomy discrepancy with humans. The study aimed to investigate the segmentation performances of 3D U-Net in: (1) generalization ability between multiple heterogeneous datasets by cross-testing experiments; (2) the compatibility when hybrid training all datasets in different sampling and encoder layer sharing schema. We further investigated the compatibility of encoder level by setting separate level for each dataset (i.e., dataset-wise convolutions) while sharing the decoder. RESULTS: Model trained on different datasets has different segmentation performance. The prediction accuracy between LiTS dataset and Zhujiang dataset was about 0.955 and 0.958 which shows their good generalization ability due to that they were all contrast-enhanced clinical patient datasets scanned regularly. For the datasets scanned under pneumoperitoneum, their corresponding datasets scanned without pneumoperitoneum showed good generalization ability. Dataset-wise convolution module in high-level can improve the dataset unbalance problem. The experimental results will facilitate researchers making solutions when segmenting those special datasets. CONCLUSIONS: (1) Regularly scanned datasets is well generalized to irregularly ones. (2) The hybrid training is beneficial but the dataset imbalance problem always exits due to the multi-domain homogeneity. The higher levels encoded more domain specific information than lower levels and thus were less compatible in terms of our datasets.
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Imageamento Tridimensional , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Aprendizado de Máquina , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Animais , Meios de Contraste , Conjuntos de Dados como Assunto , Humanos , Pneumoperitônio/diagnóstico por imagem , SuínosRESUMO
Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients. CONCLUSION: These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).
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Neoplasias dos Ductos Biliares/etiologia , Colangiocarcinoma/etiologia , Retroalimentação Fisiológica , Fator Inibidor de Leucemia/fisiologia , MicroRNAs/fisiologia , Proteínas/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transdução de SinaisRESUMO
The surgical treatment of hepatocellular carcinoma have advanced greatly in recent years: associating liver partition and portal vein ligation for staged hepatectomy can bring hope and relief to patients with advanced liver cancer and less future liver remnant; the application range of laparoscopic hepatectomy and robotic hepatectomy were amplified; hepatectomy following anatomic or non-anatomic direction should be decided by particular situations; the precise preoperative assessment of liver reserve function ensured the success of extended hepatectomy; the further discussion of United Network for Organ Sharing criteria for liver transplantation made the appearance of University of California at San Francisco, Up-to-seven and Hangzhou criteria; bridge therapy can decrease tumor progression and the dropout rate from the liver transplantation waiting list; downstaging treatment is used in selected patients with more advanced liver cancer who are beyond the accepted transplant criteria to acquire the chance of liver transplantation and increase survival rates.
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Carcinoma Hepatocelular/cirurgia , Hepatectomia , Neoplasias Hepáticas/cirurgia , Humanos , Ligadura , Transplante de Fígado , Veia Porta/cirurgia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
UNLABELLED: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effects of ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase, on HCC angiogenesis and metastasis. We found that increased expression of IF1 in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and metastasis, expressed high levels of IF1. Invasive tumors overexpressing IF1 were featured by active epithelial-mesenchymal transition (EMT) and increased angiogenesis, whereas silencing IF1 expression attenuated EMT and invasion of HCC cells. Mechanistically, IF1 promoted Snai1 and vascular endothelial growth factor (VEGF) expression by way of activating nuclear factor kappa B (NF-κB) signaling, which depended on the binding of tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) to NF-κB-inducing kinase (NIK) and the disruption of NIK association with the TRAF2-cIAP2 complex. Suppression of the NF-κB pathway interfered with IF1-mediated EMT and invasion. Chromatin immunoprecipitation assay showed that NF-κB can bind to the Snai1 promoter and trigger its transcription. IF1 was directly transcribed by NF-κB, thus forming a positive feedback signaling loop. There was a significant correlation between IF1 expression and pp65 levels in a cohort of HCC biopsies, and the combination of these two parameters was a more powerful predictor of poor prognosis. CONCLUSION: IF1 promotes HCC angiogenesis and metastasis by up-regulation of Snai1 and VEGF transcription, thereby providing new insight into HCC progression and IF1 function. (Hepatology 2014;60:1659-1673).
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , NF-kappa B/metabolismo , Neovascularização Patológica/metabolismo , Proteínas/metabolismo , Animais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , China/epidemiologia , Estudos de Coortes , Transição Epitelial-Mesenquimal , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Fosfoproteínas , Prognóstico , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismo , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas da Matriz Viral , Proteína Inibidora de ATPaseRESUMO
UNLABELLED: Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway. CONCLUSION: Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein.
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Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Colangiocarcinoma/metabolismo , Interleucina-6/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Pontos de Checagem do Ciclo Celular/fisiologia , Movimento Celular/fisiologia , Colangiocarcinoma/genética , Colangiocarcinoma/secundário , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/patologia , Valor Preditivo dos Testes , Prognóstico , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Arsenic trioxide has been demonstrated as an effective anti-cancer drug against leukemia and solid tumors both in vitro and in vivo. However, recent phase II trials demonstrated that single agent arsenic trioxide was poorly effective against hepatocellular carcinoma (HCC), which might be due to drug resistance. METHODS: Mutation detection of p53 gene in arsenic trioxide resistant HCC cell lines was performed. The therapeutic effects of arsenic trioxide and Nutlin-3 on HCC were evaluated both in vitro and in vivo. A series of experiments including MTT, apoptosis assays, co-Immunoprecipitation, siRNA transfection, lentiviral infection, cell migration, invasion, and epithelial-mesenchy-mal transition (EMT) assays were performed to investigate the underlying mechanisms. RESULTS: The acquisition of p53 mutation contributed to arsenic trioxide resistance and enhanced metastatic potential of HCC cells. Mutant p53 (Mutp53) silence could re-sensitize HCC resistant cells to arsenic trioxide and inhibit the metastatic activities, while mutp53 overexpression showed the opposite effects. Neither arsenic trioxide nor Nutlin-3 could exhibit obvious effects against arsenic trioxide resistant HCC cells, while combination of them showed significant effects. Nutlin-3 can not only increase the intracellular arsenicals through inhibition of p-gp but also promote the p73 activation and mutp53 degradation mediated by arsenic trioxide. In vivo experiments indicated that Nutlin-3 can potentiate the antitumor activities of arsenic trioxide in an orthotopic hepatic tumor model and inhibit the metastasis to lung. CONCLUSIONS: Acquisitions of p53 mutations contributed to the resistance of HCC to arsenic trioxide. Nutlin-3 could overcome arsenic trioxide resistance and inhibit tumor metastasis through p73 activation and promoting mutant p53 degradation mediated by arsenic trioxide.
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Antineoplásicos/farmacologia , Arsenicais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Imidazóis/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Óxidos/farmacologia , Piperazinas/farmacologia , Proteína Supressora de Tumor p53/genética , Animais , Trióxido de Arsênio , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Mutação , Transplante de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transdução de Sinais , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
UNLABELLED: The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world. Although sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects, currently sets the new standard for advanced HCC, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical if outcomes are to be improved. In this study we tested the hypothesis that hypoxia caused by the antiangiogenic effects of sustained sorafenib therapy could induce sorafenib resistance as a cytoprotective adaptive response, thereby limiting sorafenib efficiency. We found that HCCs, clinically resistant to sorafenib, exhibit increased intratumor hypoxia compared with HCCs before treatment or HCCs sensitive to sorafenib. Hypoxia protected HCC cells against sorafenib and hypoxia-inducible factor 1 (HIF-1α) was required for the process. HCC cells acquired increased P-gp expression, enhanced glycolytic metabolism, and increased nuclear factor kappa B (NF-κB) activity under hypoxia. EF24, a molecule having structural similarity to curcumin, could synergistically enhance the antitumor effects of sorafenib and overcome sorafenib resistance through inhibiting HIF-1α by sequestering it in cytoplasm and promoting degradation by way of up-regulating Von Hippel-Lindau tumor suppressor (VHL). Furthermore, we found that sustained sorafenib therapy led to increased intratumor hypoxia, which was associated with sorafenib sensitivity in HCC subcutaneous mice tumor models. The combination of EF24 and sorafenib showed synergistically effects against metastasis both in vivo and in vitro. Synergistic tumor growth inhibition effects were also observed in subcutaneous and orthotopic hepatic tumors. CONCLUSION: Hypoxia induced by sustained sorafenib treatment confers sorafenib resistance to HCC through HIF-1α and NF-κB activation. EF24 overcomes sorafenib resistance through VHL-dependent HIF-1α degradation and NF-κB inactivation. EF24 in combination with sorafenib represents a promising strategy for HCC.
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Compostos de Benzilideno/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Hipóxia/fisiopatologia , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Piperidonas/farmacologia , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacologia , Sorafenibe , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Interleukin 6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT-3) phosphorylation (activation) is aberrantly sustained in cholangiocarcinoma cells resulting in enhanced myeloid cell leukemia 1 (Mcl-1) expression and resistance to apoptosis. FTY720, a new immunosuppressant, derived from ISP-1, has been studied for its putative anti-cancer properties. This study aimed to elucidate the mechanism by which FTY720 mediates antitumor effects in cholangiocarcinoma (CC) cells. METHODS: Three CC cell lines were examined, QBC939, TFK-1, and HuCCT1. The therapeutic effects of FTY720 were evaluated in vitro and in vivo. Cell proliferation, apoptosis, cell cycle, invasive potential, and epithelial- mesenchy-mal transition (EMT) were examined. RESULTS: FTY720 greatly inhibited CC cells proliferation and EMT in vitro and in vivo, and this effect was associated with dephosphorylation of STAT3tyr705. FTY720 induced apoptosis and G1 phase arrest in CC cells, and inhibited invasion of CC cells. Western blot analysis showed that FTY720 induced cleavage of caspases 3, 8 and 9, and of PARP, in a dose-dependent manner, consistent with a substantial decrease in p-STAT3, Bcl-xL, Bcl-2, survivin, cyclin D1, cyclin E, N-cadherin, vimentin, VEGF and TWIST1. In vivo studies showed that tumor growth and metastasis were significantly suppressed after FTY720 treatment. CONCLUSIONS: These results suggest that FTY720 induces a significant decrease in p-STAT3, which inhibits proliferation and EMT of CC cells, and then induces G1 phase arrest and apoptosis. We have characterized a novel immunosuppressant, which shows potential anti-tumor effects on CC via p-STAT3 inhibition. FTY720 merits further investigation and warrants clinical evaluation.
Assuntos
Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Propilenoglicóis/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Esfingosina/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An innovative organic small molecule with a D-A structure was synthesized by connecting triphenylamine to BODIPY via a thiophene bridge. Triphenylamine and thiophene units ingeniously modulate the balance between steric hindrance and π-π interactions around the flat aza-BODIPY core. The molecule exhibits near-infrared fluorescence absorption and emits at roughly 1100 nm, featuring a significant Stokes shift. Both the molecule and its nanoparticles demonstrate high stability and achieve a remarkable 35 % photothermal conversion efficiency when conjugated with the P(OEGMA)20-P(Asp)14 copolymer. In vitro assessments show low dark toxicity and outstanding biocompatibility. Moreover, in vivo studies and photothermal therapy in mice indicate substantial tumor shrinkage and reduced recurrence, confirming its potential in cancer treatment. These results highlight the promise of this organic molecule and its nanoparticles for NIR-II imaging-guided photothermal therapy, introducing a novel approach to phototheranostic applications for cancer management.
Assuntos
Compostos de Boro , Corantes Fluorescentes , Raios Infravermelhos , Nanopartículas , Peptídeos , Nanopartículas/química , Compostos de Boro/química , Animais , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Camundongos , Humanos , Peptídeos/química , Nanomedicina Teranóstica/métodos , Terapia Fototérmica , Camundongos Endogâmicos BALB C , FototerapiaRESUMO
Photothermal therapy (PTT) has attracted attention as a highly effective non-invasive treatment method. However, the high localized temperatures (>50 °C) required for its treatment will inevitably cause damage to the surrounding normal tissues. Therefore, it is important to develop novel and effective strategies to achieve mild photothermal therapy (mPTT). The overexpression of heat shock proteins (HSPs), a widespread heat stress protein, leads to the generation of heat resistance in cancer cells, which seriously affects the therapeutic effect. Thus, inhibiting the expression of HSPs to reduce the heat resistance of tumor cells is expected to enhance the therapeutic effect of mPTT. Here, we successfully synthesized a fluorescent probe bonded with an amphiphilic polypeptide to a cyanine dye and achieved physical encapsulation of the blocker SB705498 through a self-assembly process. SB705498 promotes transient receptor potential vanilloid member 1 (TRPV1) channel blockade that can inhibit the translocation of the heat shock transcription factor 1 (HSF 1) by blocking the influx of calcium and thus affecting the expression of HSPs, which has the potential to enhance the thermotherapy of cancer under mild conditions. In addition, the nanoparticles enabled NIR-II fluorescence imaging with good stability and high photothermal conversion efficiency (48.10â¯%). Therefore, this study provides a new strategy for realizing precise mPTT(<45 °C) guided by NIR-II imaging. STATEMENT OF SIGNIFICANCE: Inhibition of overexpression of heat shock proteins (HSPs) in cancer photothermal therapy (PTT) is expected to enhance the therapeutic effect of mild photothermal therapy (mPTT). In this study, we synthesized a fluorescent probe bonded to cyanine dyes with amphiphilic polypeptides and physically wrapped the blocker SB705498 through a self-assembly process. As a transient receptor potential vanillin 1 (TRPV1) channel blocker, SB705498 inhibits heat shock transcription factor 1 (HSF1) translocation by blocking calcium ion influx, thereby improving mPTT efficacy by inhibiting the expression of HSPs. The nanoparticles also enable NIR-II fluorescence imaging with good stability and high photothermal conversion efficiency (48.10â¯%). Thus, this study provides a new strategy for NIR-II mPTT.
Assuntos
Raios Infravermelhos , Nanopartículas , Peptídeos , Terapia Fototérmica , Canais de Cátion TRPV , Nanopartículas/química , Canais de Cátion TRPV/metabolismo , Humanos , Peptídeos/química , Peptídeos/farmacologia , Nanomedicina Teranóstica/métodos , Animais , Corantes Fluorescentes/química , Fatores de Transcrição de Choque Térmico/metabolismo , Linhagem Celular Tumoral , Camundongos , Camundongos NusRESUMO
Stable organic radicals have emerged as a promising option to enhance fluorescence quantum yield (QY), gaining traction in medical treatment due to their unique electronic transitions from the ground state (D0) to the doublet excited state (D1). We synthesized a stable dicyanomethyl radical with a NIR-II fluorescence QY of 0.86 %, surpassing many NIR-II organic dyes. Subsequently, amphiphilic polymer-encapsulated nanoparticles (NPs) containing the radical were created, achieving a NIR-II fluorescence QY of 0.32 %, facilitating high-contrast bio-imaging. These CNPPs exhibit self-enhanced photothermal properties, elevating photothermal conversion efficiency (PCE) from 43.5 % to 57.5 % under 915 nm laser irradiation. This advancement enables more efficient photothermal therapy (PTT) with lower dye concentrations and reduced laser power, enhancing both feasibility and safety. Through regular fractionated mild photothermal therapy, we observed the release of damage-associated molecular patterns (DAMPs) and an increase in cytokine expression, culminating in combined mild phototherapy (m-PTT)-mediated immunogenic cell death (ICD). Consequently, we developed an immunostimulatory tumor vaccine, showcasing a novel approach for refining photothermal agents (PTA) and optimizing the PTT process.
Assuntos
Raios Infravermelhos , Nanopartículas , Peptídeos , Nanopartículas/química , Peptídeos/química , Peptídeos/farmacologia , Animais , Humanos , Camundongos , Nanomedicina Teranóstica , Tamanho da Partícula , Terapia Fototérmica , Fototerapia , Radicais Livres/química , Propriedades de Superfície , Sobrevivência Celular/efeitos dos fármacosRESUMO
Rapid propagation of tumor cells requires plenty of energy, which is adenosine triphosphate (ATP) dependent. ATP inhibition in tumors not only results in the starvation of tumor cells but also down-regulation of the level of heat shock proteins (HSPs), which usually increase during traditional photothermal therapy (PTT), especially when the temperature is up 50 °C. 2-deoxy-D-glucose (2DG) is an anti-glycolytic reagent and can be used as an efficient agent for ATP inhibition in tumors. Compared with typical PTT, low-temperature mild photothermal therapy (MPTT) is receiving more and more attention because it avoids the high temperatures causing damage to the normal tissue, and the increase of HSPs which decrease PTT. Here, multifunctional polypeptide nanoparticles pDG@Ahx conjugating both a NIR probe Ahx-BDP and 2DG into the side chain of the amphiphilic polypeptide have been prepared. In vitro and in vivo studies reveal that the as-prepared nanoparticles achieve a synergistic effect of starvation/MPTT/PDT (photodynamic therapy), and it provides a new strategy to NIR-I/II fluorescence imaging-guided starvation/MPTT/PDT synergy therapy for tumors.
RESUMO
NIR-IIa fluorescence imaging (FI) and NIR-II photothermal therapy (PTT) have gained popularity due to the advantages of high temporal and spatial resolution and deep penetration. However, the hyperthermia (>48 °C) of conventional PTT with nonspecific warming and thermal diffusion may inevitably cause damage to healthy tissues or organs surrounding the tumor. Therefore, it is highly desirable to provide effective cancer treatment by implementing mild photothermal therapy (mPTT) at mild temperatures with lower laser power density. Here, the nanotheranostic platform FN@P-GA NPs with NIR-II absorption and NIR-IIa emission was developed by constructing J-aggregates. FN@P-GA possesses good biocompatibility, favorable NIR-IIa FI performance, decent stability, and high photothermal conversion efficiency (57.6 %), which lays a solid foundation for FI-guided mPTT. Due to its ability to effectively down-regulate the expression of HSP90 and reduce cellular thermoresistance to kill cancer cells, FN@P-GA successfully achieved NIR-IIa FI-guided mPTT and demonstrated its potent anti-tumor effect under 1064 nm laser irradiation at mild temperature and low power density (0.3 W/cm2).
Assuntos
Carbocianinas , Corantes Fluorescentes , Raios Infravermelhos , Terapia Fototérmica , Humanos , Carbocianinas/química , Carbocianinas/farmacologia , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Animais , Camundongos , Imagem Óptica , Sobrevivência Celular/efeitos dos fármacos , Tamanho da Partícula , Antineoplásicos/química , Antineoplásicos/farmacologia , Propriedades de Superfície , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Nanopartículas/química , Fluorescência , Linhagem Celular TumoralRESUMO
Caroli disease (CD) is a congenital disease of the intrahepatic biliary system, which manifests as cystic dilatation of the intrahepatic bile ducts. The disease has a low incidence and atypical clinical manifestations; therefore, it can be easily misdiagnosed. Hepatitis B infection is a viral infection that affects liver cells, leading to degeneration, necrosis, and regeneration of the cells and formation of false lobules, and ultimately nodular cirrhosis, which can lead to liver dysfunction and liver failure. Herein, we report a case of decompensated liver cirrhosis because of a diffuse form of CD, which was misdiagnosed because of long-term hepatitis B virus (HBV) infection. Finally, orthotopic liver transplantation (OLT) was performed, and the patient was cured. We believe that this congenital factor combined with HBV infection accelerated cirrhosis progression in this patient. This transplant was carried out in accordance with the Helsinki Congress and the Declaration of Istanbul.