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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120336, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34481256

RESUMO

New precise, responsive and selective univariate and multivariate chemometric spectrophotometric methods were developed and validated for determination of vandetanib (VTB), dasatinib (DTB), and sorafenib (SFB) in pure form, tablets, spiked human (plasma and urine). Determination of these drugs is essential because of their therapeutic benefits. These methods included double divisor ratio spectra derivative univariate method and chemometric multivariate method including partial least-squares (PLS) and principal component regression (PCR). A novel univariate method was developed for the estimation of these drugs. This method depends on the UV-Spectrophotometric data for simultaneous analysis of a ternary overlapped mixture. The Double divisor ratio spectra derivative absorption minima at 358.4 nm was used for quantification of VTB, absorption maxima at 300.3 nm for quantification of DTB and absorption maxima at 259.8 nm for quantification of SFB. This method shown a linearity in the extent of 2-9 µg/mL for VTB and DTB and over the concentration range of 3-9 µg/mL SFB within correlation coefficient (r2) of 0.9999. This method was successfully applied to pure form, tablet dosage form, spiked human (urine and plasma). Chemometric PLS and PCR models were found to be linear in the range of 2-9, 2-9, and 3-9 µg/mL for VTB, DTB and SFB, respectively. These models were estimated using eighteen mixtures as calibration set and seven mixtures as validation set. In the original data, the minimum root mean square error of prediction (RMSEP) was 0.11, 0.09 and 0.09 for VTB, DTB and SFB by PLS and 0.05, 0.04 and 0.03 by PCR while in the derivative data, the RMSEP was 0.09, 0.10 and 0.09 by PLS and 0.06, 0.06 and 0.03, by PCR for VTB, DTB and SFB, respectively. These methods were applied for the determination of the drugs in pure form and dosage form. Updating PLS model permitted the determination of the VTB, DTB and SFB in spiked human urine, plasma and drug-dissolution test of their tablet.


Assuntos
Quinazolinas , Calibragem , Dasatinibe , Humanos , Análise dos Mínimos Quadrados , Piperidinas , Sorafenibe , Espectrofotometria
2.
DNA Cell Biol ; 40(11): 1418-1427, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34767735

RESUMO

In this study, we examined the regulatory role of CCDC34 in the sorafenib sensitivity of hepatocellular carcinoma (HCC) and its functional partners. Wide-type Huh7 and Hep3B and induced sorafenib-resistant (SR) Huh7/SR and Hep3B/SR cells were used as in vitro cell models. Immunofluorescent staining and coimmunoprecipitation were performed to check protein-protein interaction. Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL), PI/Annexin V staining, and western blot analysis were performed to assess cell response to sorafenib. The results showed that CCDC34 upregulation in HCC was associated with poor survival. Huh7/SR and Hep3B/SR cells had significantly higher CCDC34 expression than the parental cell lines. RABL2A expression was significantly upregulated in SR HCC cells and interacted with CCDC34 in its GTP-bound state in Huh7/SR and Hep3B/SR cells. RABL2A depletion sensitized Huh7/SR and Hep3B/SR cells to sorafenib. RABL2A Q80L mutant (GTP-bound state locked), but not S35N mutant (GDP-bound state locked) overexpression increased sorafenib IC50 of Huh7 and Hep3B cells. CCDC34 depletion nearly abrogated the protective effects of RABL2A Q80L overexpression both in vitro and in vivo. RABL2A Q80L overexpression significantly increased the expression of p-p38 and p-JNK, the effects of which were significantly attenuated by CCDC34 depletion. In summary, we infer that the RABL2A-CCDC34 axis plays an important role in mediating p38/MAPK and JNK/MAPK signaling, thereby contributing to acquired sorafenib resistance in HCC.


Assuntos
Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Neoplasias/metabolismo , Sorafenibe/metabolismo , Antígenos de Neoplasias/fisiologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , China , Resistencia a Medicamentos Antineoplásicos/fisiologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/fisiologia
3.
Phytomedicine ; 92: 153740, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34600176

RESUMO

BACKGROUND: Vasculogenic mimicry (VM) is a newly described tumor vascular phenomenon that is independent of traditional angiogenesis and provides an adequate blood supply for tumor growth. VM has been consistently observed in different cancer types. Hence, inhibition of VM may be considered a new anticancer therapeutic strategy. PURPOSE: This study aimed to elucidate the potential anticancer effect of daurisoline (DS) on hepatocellular carcinoma (HCC) and the potential molecular mechanism by which DS inhibits VM. We also verified whether combination treatment with sorafenib and DS constitutes a novel therapeutic approach to prevent HCC progression. METHODS: The effects of DS on proliferation were evaluated by Cell Counting Kit-8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays. 4',6-Diamidino-2-phenylindole (DAPI) staining and flow cytometric analysis were employed to investigate its effects on apoptosis. Western blot analysis, Matrigel tube formation assays, pulldown assays and immunofluorescence staining were applied to validate the potential mechanism by which DS inhibits VM. Mouse xenograft models were used to evaluate anticancer activities. RESULTS: DS inhibited HCC cell proliferation, induced HCC cell apoptosis and repressed VM formation by inactivating RhoA/ROCK2-mediated AKT and ERK-p38 MAPK signaling. Additionally, DS dramatically sensitized HCC cell lines to sorafenib, a curative anticancer drug for patients with advanced HCC. CONCLUSIONS: Our study provides insights into the molecular mechanisms underlying DS-induced inhibition of VM, which may facilitate the development of a novel clinical anti-HCC drug. Moreover, our findings suggest that the combination of DS and sorafenib constitutes a potential therapeutic strategy for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Benzilisoquinolinas , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Neovascularização Patológica/tratamento farmacológico , Sorafenibe/farmacologia
4.
Biomacromolecules ; 22(11): 4814-4822, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34677048

RESUMO

Targeted molecular therapy, for example, with sorafenib (SF) is considered as a new and potent strategy for glioblastoma (GBM) that remains hard to treat today. Several clinical trials with SF, as monotherapy or combination therapy with current treatments, have not met the clinical endpoints, likely as a result of the blood-brain barrier (BBB) and inferior GBM delivery. Here, we designed and explored small, smart, and LDLR-specific micelles to load SF (LDLR-mSF) and to improve SF therapy of GBM by enhancing BBB penetration, GBM accumulation, and cell uptake. LDLR-mSF with 2.5% ApoE peptide functionality based on poly(ethylene glycol)-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate exhibited nearly quantitative SF loading, small size (24 nm), high colloidal stability, and glutathione-activated SF release. The in vitro and in vivo studies certified that LDLR-mSF greatly enhanced BBB permeability and U-87 MG cell uptake and caused 10.6- and 12.9-fold stronger anti-GBM activity and 6.0- and 2.5-fold higher GBM accumulation compared with free SF and non-LDLR mSF controls, respectively. The treatment of an orthotopic human GBM tumor model revealed that LDLR-mSF at a safe dosage of 15 mg of SF/kg significantly retarded tumor progression and improved the survival rate by inducing tumor cell apoptosis and inhibiting tumor angiogenesis. These small, smart, and LDLR-specific micelles provide a potential solution to enhance targeted molecular therapy of GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Micelas , Sorafenibe/farmacologia
5.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502061

RESUMO

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract and tends to have a poor prognosis due to its invasive potential. Recent studies have reported that up to 80% of canine urothelial carcinoma has the BRAF V595E mutation, which is homologous to the human V600E mutation. Activating the BRAF mutation is an actionable target for developing effective therapeutic agents inhibiting the BRAF/mitogen-activated protein kinase (MAPK) pathway in canine cancer as well as human cancer. We established novel canine TCC cell lines from two tumor tissues and one metastatic lymph node of canine TCC patients harboring the BRAF V595E mutation. Tumor tissues highly expressed the BRAF mutant and phosphorylated extracellular signal-related kinases (ERK)1/2 proteins. The derived cell lines demonstrated activated MAPK pathways. We also evaluated the cell lines for sensitivity to BRAF inhibitors. Sorafenib, a multiple kinase inhibitor targeting RAF/vascular endothelial growth factor receptor (VEGFR), successfully inhibited the BRAF/MAPK pathway and induced apoptosis. The established canine TCC cell lines responded with greater sensitivity to sorafenib than to vemurafenib, which is known as a specific BRAF inhibitor in human cancer. Our results demonstrated that canine TCC cells showed different responses compared to human cancer with the BRAF V600E mutation. These cell lines would be valuable research materials to develop therapeutic strategies for canine TCC patients.


Assuntos
Carcinoma de Células de Transição/veterinária , Técnicas de Cultura de Células/veterinária , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Urológicas/veterinária , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Técnicas de Cultura de Células/métodos , Células Cultivadas , Cães , Feminino , Camundongos , Mutação , Sorafenibe/uso terapêutico , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
J Med Case Rep ; 15(1): 481, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34544494

RESUMO

BACKGROUND: Sorafenib is an oral multikinase inhibitor that targets Raf serine/threonine receptor tyrosine kinases and inhibits tumor cell growth and angiogenesis. Cutaneous toxicities of sorafenib are common, including cutaneous eruptions (such as truncal erythema and seborrheic-dermatitis-like changes) and hand-foot syndrome. Keratoacanthomas and squamous cell carcinomas have been reported previously; however, we report a case of multiple eruptive keratoacanthomas in the form of Grzybowski syndrome after initiation of sorafenib. CASE PRESENTATION: We report a 63-year-old Caucasian male who developed multiple cutaneous eruptive keratoacanthomas after starting sorafenib 400 mg twice daily. He had a known history of hepatitis-C-related cirrhosis and hepatocellular carcinoma, and previously had actinic keratosis and skin squamous cell carcinoma excision. Approximately two and a half months after starting sorafenib, the patient initially developed two lesions, one on each forearm, and after excision, these lesions demonstrated histological features of squamous cell carcinoma. One month later, the patient presented with approximately 48 new skin lesions of varying size on the back, bilateral upper limbs, and face requiring excisional biopsy of a large number of these lesions. Histopathology showed eruptive invasive keratoacanthomas (Grzybowski syndrome). Sorafenib was temporarily stopped and subsequently restarted at a lower dose. Acitretin 25 mg daily was commenced after few weeks, and no further keratoacanthomas developed during his treatment. CONCLUSIONS: We report a unique case of sorafenib-associated Grzybowski syndrome. Temporary interruption and dose reduction of sorafenib and use of acitretin appeared to prevent further development of keratoacanthomas.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Exantema , Ceratoacantoma , Dermatopatias , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Ceratoacantoma/induzido quimicamente , Ceratoacantoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Sorafenibe/efeitos adversos
8.
Medicine (Baltimore) ; 100(38): e27013, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559096

RESUMO

BACKGROUND: The present network meta-analysis was conducted to perform an indirect comparison among ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma (HCC) progressed on sorafenib treatment. METHODS: A systematic review through Medline, Embase, and Cochrane library was developed, with eligible randomized clinical trials been included. Hazard ratios (HRs) including progression-free survival (PFS), overall survival (OS), odds ratios of disease control rate (DCR), objective response rate (ORR), and adverse events were compared indirectly with network meta-analysis using random model in software STATA version 13.0. RESULTS: A total of 4 randomized clinical trials including 2137 patients met the eligibility criteria and enrolled. Indirect comparisons showed that there was no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among agents of regorafenib, cabozantinib, and ramucirumab in advanced HCC patients with elevated α-fetoprotein (AFP) (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib was the only agent associated with significant superiority in OS, compared with placebo (hazard ratio 0.67, 95% CI, 0.50-0.90). CONCLUSIONS: The present network meta-analysis revealed that there might be no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among regorafenib, cabozantinib, or ramucirumab in advanced HCC patients with elevated AFP (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib might be associated with significant superiority in OS, compared to placebo, which need further investigation in clinical practice.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/secundário , Esquema de Medicação , Humanos , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe/administração & dosagem , Sorafenibe/uso terapêutico
9.
PLoS One ; 16(9): e0256755, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34473785

RESUMO

BACKGROUND AND AIM: As a multiple tyrosine kinase inhibitor, sorafenib is widely used to treat hepatocellular carcinoma (HCC), but patients frequently face resistance problems. Because the mechanism controlling sorafenib-resistance is not well understood, this study focused on the connection between tumor characteristics and the Nrf2 signaling pathway in a sorafenib-resistant HCC cell line. METHODS: A sorafenib-resistant HCC cell line (Huh7) was developed by increasing the dose of sorafenib in the culture medium until the target concentration was reached. Cell morphology, migration/invasion rates, and expression of stemness-related and ATP-binding cassette (ABC) transporter genes were compared between sorafenib-resistant Huh7 cells and parental Huh7 cells. Next, a small interfering RNA was used to knock down Nrf2 expression in sorafenib-resistant Huh7 cells, after which cell viability, stemness, migration, and ABC transporter gene expression were examined again. RESULTS: Proliferation, migration, and invasion rates of sorafenib-resistant Huh7 cells were significantly increased relative to the parental cells with or without sorafenib added to the medium. The expression levels of stemness markers and ABC transporter genes were up-regulated in sorafenib-resistant cells. After Nrf2 was knocked down in sorafenib-resistant cells, cell migration and invasion rates were reduced, and expression levels of stemness markers and ABC transporter genes were reduced. CONCLUSION: Nrf2 signaling promotes cancer stemness, migration, and expression of ABC transporter genes in sorafenib-resistant HCC cells.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Movimento Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Expressão Gênica , Neoplasias Hepáticas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/genética , Sorafenibe/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos , Transfecção
10.
Anticancer Res ; 41(9): 4215-4228, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475041

RESUMO

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) are used for the treatment of both wild type and mutant non-small cell lung cancer (NSCLC); however, acquired resistance is a major clinical challenge. Herein, we aimed to investigate the effects of telmisartan (Tel), CFM 4.16 and sorafenib combination in rociletinib resistant NSCLC tumors. MATERIALS AND METHODS: 3D spheroid cultures and western blotting were used for evaluating cytotoxic effects and protein expression. An in vivo rociletinib resistant H1975 xenograft model of NSCLC was developed by subcutaneous injection of rociletinib resistant H1975 cells into nude mice. RESULTS: Tel, CFM 4.16 and sorafenib combination displayed superior anti-cancer effects in 3D spheroid cultures and a rociletinib resistant H1975 xenograft model of NSCLC by decreasing the protein expression of oncogenic and cancer stem cell markers (Nanog, Sox2 and Oct4). CONCLUSION: Tel facilitates effective penetration of CFM 4.16 and sorafenib in rociletinib resistant H1975 models of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Esferoides Celulares/citologia , Compostos de Espiro/administração & dosagem , Telmisartan/administração & dosagem , Tiadiazóis/administração & dosagem , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Compostos de Espiro/farmacologia , Telmisartan/farmacologia , Tiadiazóis/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
World J Gastroenterol ; 27(32): 5424-5437, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34539142

RESUMO

BACKGROUND: Sorafenib is an oral drug that prolongs overall survival (OS) in patients with hepatocellular carcinoma. Adverse events, including hand-foot skin reaction (HFSR), lead to permanent sorafenib discontinuation. AIM: To clarify the association between interventions for adverse events and patient prognosis. METHODS: We performed a retrospective, multicenter study of patients treated with sorafenib monotherapy between May 2009 and March 2018. We developed a mutual cooperation system that was initiated at the start of sorafenib treatment to effectively manage adverse events. The mutual cooperation system entailed patients receiving consultations during which pharmacists provided accurate information about sorafenib to alleviate the fear and anxiety related to adverse events. We stratified the patients into three groups: Group A, patients without HFSR but with pharmacist intervention; Group B, patients with HFSR and pharmacist interventions unreported to oncologists (nonmutual cooperation system); and Group C, patients with HFSR and pharmacist interventions known to oncologists (mutual cooperation system). OS and time to treatment failure (TTF) were evaluated using the Kaplan-Meier method. RESULTS: We enrolled 134 patients (Group A, n = 41; Group B, n = 30; Group C, n = 63). The median OS was significantly different between Groups A and C (6.2 vs 13.9 mo, p < 0.01) but not between Groups A and B (6.2 vs 7.7 mo, P = 0.62). Group A vs Group C was an independent OS predictor (HR, 0.41; 95%CI: 0.25-0.66; P < 0.01). In Group B alone, TTF was significantly lower and the nonadherence rate was higher (P < 0.01). In addition, the Spearman's rank correlation coefficients between OS and TTF in each group were 0.41 (Group A; P < 0.01), 0.13 (Group B; P = 0.51), and 0.58 (Group C; P < 0.01). There was a highly significant correlation between OS and TTF in Group C. However, there was no correlation between OS and TTF in Group B. CONCLUSION: The mutual cooperation system increased treatment duration and improved prognosis in patients with HFSR. Future prospective studies (e.g., randomized controlled trials) and improved adherence could help prevent OS underestimation.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Estudos Prospectivos , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Resultado do Tratamento
12.
Curr Opin Pharmacol ; 60: 141-148, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418875

RESUMO

The landscape of hepatocellular carcinoma (HCC) has changed since the incorporation of sorafenib in 2007 as the first pharmacological treatment for HCC. The combination of atezolizumab plus bevacizumab is currently the first-line treatment for HCC patients, and there are several second-line options approved for patients who had received sorafenib as the first-line treatment. The advantage of having multiple options of pharmacological treatment for HCC patients is associated to the need to redefine the clinical decision-making approach and considering new endpoints for the clinical trials design. The aim of this review was to share the Barcelona Clinic Liver Cancer approach and to summarize the ongoing clinical trials, which are testing pharmacological treatments.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico
13.
Hepatol Int ; 15(5): 1268-1277, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34415515

RESUMO

PURPOSE: To investigate the efficacy of sequential apatinib treatment in patients with unresectable hepatocellular carcinoma (HCC) refractory to sorafenib-transarterial chemoembolization (TACE). MATERIALS AND METHODS: This respective study was conducted on 95 consecutive patients with sorafenib-TACE-refractory unresectable HCC in our center from January 2014 to December 2019. According to the response to sorafenib-TACE treatment and the subsequent management, the eligible patients were assigned into three groups: sorafenib-TACE (ST) group, sorafenib-TACE-apatinib (STA) group, and sorafenib-TACE-supportive care (STS) group. The differences in overall survival (OS) and tumor response were compared among the three groups. Risk factors related to prognosis were analyzed. RESULTS: A total of 58 patients were enrolled in the study, with 11, 15, and 28 patients in ST, STA, and STS group, respectively. The median OS of the STA group was significantly improved when compared with the STS group, either from the start of sorafenib-TACE resistance or the initiation of sorafenib-TACE therapy (14.0 versus 4.0 months, p = 0.003; 19.0 versus 9.0 months, p < 0.001; respectively). Additionally, from the start of sorafenib-TACE treatment, the median OS of the STA group was longer than that of the ST group without statistical difference (19.0 versus 15.0 months, p = 0.28), so did the comparison of median OS between the ST group and the STS group (15.0 versus 9.0 months, p = 0.06). Extrahepatic metastases were an independent risk factor for poor prognosis. CONCLUSION: In patients with sorafenib-TACE-refractory HCC, subsequent apatinib treatment significantly improved the OS when compared with supportive care, and produced comparative outcomes with those sorafenib-TACE responders.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Terapia Combinada , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Piridinas , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Resultado do Tratamento
14.
In Vivo ; 35(5): 2969-2974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410996

RESUMO

BACKGROUND: We report two cases in which severe skin disorders developed during sorafenib treatment in patients with renal cell carcinoma (RCC) who had previously received nivolumab. CASE REPORT: Case 1: A 50-year-old man with RCC received nivolumab as the fifth-line therapy followed by sorafenib as the sixth-line therapy. On day 15 of sorafenib administration, the patient was hospitalized with systemic erythema multiforme, acne-like skin rash, and hand-foot syndrome. Case 2: A 40-year-old man with RCC received nivolumab as the second-line therapy followed by sorafenib as the fifth-line treatment. On day 12 of sorafenib administration, the patient was hospitalized with an acne-like skin rash and hand-foot syndrome. The skin disorders in the two cases improved within 2-3 weeks after sorafenib discontinuation and the start of treatment with topical and oral steroids. CONCLUSION: When using sorafenib in patients previously treated with nivolumab, close attention should be paid to the onset of serious skin disorders.


Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Adulto , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Nivolumabe/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Sorafenibe/efeitos adversos , Resultado do Tratamento
15.
Medicine (Baltimore) ; 100(31): e26820, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397843

RESUMO

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.


Assuntos
Bilirrubina/análise , Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Albumina Sérica/análise , Sorafenibe , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Farmacológicos/análise , Proteína C-Reativa/análise , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Correlação de Dados , Monitoramento de Medicamentos/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Japão/epidemiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos
16.
Cancer Sci ; 112(10): 4100-4111, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34339558

RESUMO

SHANK-associated RH domain interacting protein (SHARPIN) plays an important role in carcinogenesis, as well as inflammation and immunity. Our study explored the effects and underlying mechanisms of SHARPIN in clear cell renal cell carcinoma (ccRCC). By analyzing The Cancer Genome Atlas database, we found that upregulated SHARPIN in patients with ccRCC led to a poor prognosis. Semiquantitative immunohistochemical analysis of clinical samples was carried out and the results suggested the positive association between SHARPIN and hypoxia-induced factor-2α (HIF-2α). Von Hippel-Lindau protein (pVHL) is a tumor suppressor that contributes to degrading HIF-2α. Mechanically, SHARPIN promoted the ubiquitination and proteasomal degradation of pVHL, resulting in the sustained activation of HIF-2α. The α and ß domains of pVHL and ubiquitin-like domain of SHARPIN are required for the interaction. The knockdown of SHARPIN effectively inhibited acquired sorafenib resistance in ccRCC cell lines and tumor growth in xenograft models. In conclusion, our work reveals a novel posttranslational regulation of SHARPIN on pVHL, indicating that SHARPIN could be a potential target for ccRCC treatment.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Ubiquitinas/fisiologia , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Inativação Gênica , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional , Proteólise , RNA Interferente Pequeno , Distribuição Aleatória , Sorafenibe/farmacologia , Ubiquitinação , Ubiquitinas/genética , Ubiquitinas/metabolismo , Regulação para Cima
17.
J Biomed Sci ; 28(1): 56, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34340705

RESUMO

BACKGROUND: Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. METHODS: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model. RESULTS: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3'-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of ß-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1. CONCLUSIONS: PAK5 contributed to the sorafenib resistant characteristics of HCC via ß-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Animais , Antineoplásicos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
18.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359884

RESUMO

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Reprogramação Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Hipóxia/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Reprogramação Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Sorafenibe/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
19.
Exp Cell Res ; 406(1): 112755, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34332981

RESUMO

Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically up-regulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor 'SP'600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be beneficial for further clinical application of sorafenib in liver cancer treatment.


Assuntos
Ácido Dicloroacético/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Hepáticas/tratamento farmacológico , MAP Quinase Quinase 4/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Sorafenibe/farmacologia , Acetilcisteína/farmacologia , Animais , Antracenos/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
World J Gastroenterol ; 27(28): 4667-4686, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366628

RESUMO

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proteínas de Transporte , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sorafenibe/farmacologia , Proteína 1 de Ligação a Y-Box
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