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1.
Nat Commun ; 11(1): 5060, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033246

RESUMO

Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.


Assuntos
Sistemas CRISPR-Cas/genética , Neoplasias/genética , Fusão Oncogênica/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Doxorrubicina/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Deleção de Genes , Loci Gênicos , Instabilidade Genômica , Células HEK293 , Humanos , Íntrons/genética , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , RNA Guia/metabolismo , Reprodutibilidade dos Testes , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(8): 1200-1206, 2020 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895183

RESUMO

OBJECTIVE: To investigate the difference of tumor formation in different mouse strains bearing patient-derived xenograft of esophageal squamous cell carcinoma(ESCC) and establish a better animal model for preclinical study of individualized treatment of ESCC. METHODS: The tumor tissues collected from 22 ESCC patients were used to establish tumor-bearing mouse models in B-NDG? (NSG) mice and BALB/c nude mice. The tumor formation rate and tumor formation time were compared between the two mouse models, and HE staining, immunohistochemistry and genome sequencing were carried out to assess the consistency between transplanted tumor tissues in the models and patient-derived tumor tissues. RESULTS: The tumor-bearing models were established successfully in both NSG mice (50%, 11/22) and BALB/c nude mice (18.18%, 4/22). The average tumor formation time was significantly shorter in NSG mice than in BALB/c nude mice (75.95 vs 91.67 days, P < 0.001). In both of the mouse models, the transplanted tumors maintained morphological characteristics identical to those of patient-derived ESCC tumors. Genetic analysis showed that the xenografts in NSG mice had a greater genetic similarity to the patients' tumors than those in BALB/c nude mice (P < 0.0001). CONCLUSIONS: Mouse models bearing xenografts of patient-derived ESCC can be successfully established in both NSG mice and BALB/c nude mice, but the models in the former mouse strain can be more reliable.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Linhagem Celular Tumoral , Proliferação de Células , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Commun ; 11(1): 4629, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934208

RESUMO

Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.


Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Rabdomiossarcoma/metabolismo , Animais , Bancos de Espécimes Biológicos , Perfilação da Expressão Gênica , Humanos , Fenótipo , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Células Tumorais Cultivadas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nat Commun ; 11(1): 4530, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913195

RESUMO

Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation.


Assuntos
Cloretos/administração & dosagem , Portadores de Fármacos/química , Compostos de Ouro/administração & dosagem , Ouro/química , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Animais , Biomineralização/efeitos da radiação , Feminino , Ouro/efeitos da radiação , Humanos , Hipertermia Induzida/métodos , Íons , Células MCF-7 , Nanopartículas Metálicas/efeitos da radiação , Camundongos , Fotoquimioterapia/métodos , Polietilenoglicóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Anticancer Res ; 40(9): 5049-5057, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878793

RESUMO

BACKGROUND/AIM: Studies with acridine compounds have reported anticancer effects. Herein, we evaluated the toxicity and antitumor effect of the (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a promising anticancer spiro-acridine compound. MATERIALS AND METHODS: The toxicity of AMTAC-06 was evaluated on zebrafish and mice. Antitumor activity was assessed in Ehrlich ascites carcinoma model. Effects on angiogenesis, cytokine levels and cell cycle were also investigated. RESULTS: AMTAC-06 did not induce toxicity on zebrafish and mice (LD50 approximately 5000 mg/kg, intraperitoneally). No genotoxicity was observed on micronucleus assay. AMTAC-06 significantly reduced the total viable Ehrlich tumor cells and increased sub-G1 peak, suggesting apoptosis was triggered. Moreover, the compound significantly decreased the density of peritumoral microvessels, indicating an anti-angiogenic action, possibly dependent on the cytokine modulation (TNF-α, IL-1ß and IFN-γ). No significant toxicological effects were recorded for AMTAC-06 on tumor transplanted animals. CONCLUSION: AMTAC-06 has low toxicity and a significant antitumor activity.


Assuntos
Acridinas/farmacologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Compostos de Espiro/farmacologia , Acridinas/química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/química , Imunomodulação/efeitos dos fármacos , Camundongos , Estrutura Molecular , Compostos de Espiro/química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
7.
Anticancer Res ; 40(9): 5059-5069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878794

RESUMO

BACKGROUND/AIM: Liver cancer is the fourth leading cause of cancer-related mortality globally, of which hepatocellular carcinoma (HCC) accounts for 85-90% of total primary liver cancer. A drug shortage for HCC therapy triggered us to screen the small-molecule database with a high-throughput cellular screening system. Herein, we examined whether cetyltrimethylammonium bromide (CTAB) inhibits cellular mobility and invasiveness of Mahlavu HCC cells. MATERIALS AND METHODS: The effects of CTAB on cell viability were assessed using WST-1 assay, cell-cycle distribution using flow cytometric analysis, migration/invasion using woundhealing and transwell assays, and associated protein levels using western blotting. RESULTS: Treatment of Mahlavu cells with CTAB transformed its mesenchymal spindle-like morphology. In addition, CTAB exerted inhibitory effects on the migration and invasion of Mahlavu cells dose-dependently. CTAB also reduced the protein levels of matrix metalloproteinase-2 (MMP2), MMP9, RAC family small GTPase 1, SNAIL family transcriptional repressor 1 (SNAI1), SNAI2, TWIST family basic helix-loop-helix transcription factor 1 (TWIST1), vimentin, N-cadherin, phospho-fibroblast growth factor (FGF) receptor, phospho-phosphoinositide 3-kinase, phospho-v-Akt murine thymoma viral oncogene and phospho-signal transducer and activator of transcription 3 but increased the protein levels of tissue inhibitor of metalloproteinases-1/2 and E-cadherin. Rescue experiments proved that CTAB induced mesenchymal-epithelial transition in Mahlavu cells and this was significantly dose-dependently mitigated by basic FGF. CONCLUSION: CTAB suppressed the migration and invasion of Mahlavu cells through inhibition of the FGF signaling pathway. CTAB seems to be a potential agent for preventing metastasis of hepatic cancer.


Assuntos
Antineoplásicos/farmacologia , Cetrimônio/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Anticancer Res ; 40(9): 5081-5090, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878796

RESUMO

BACKGROUND/AIM: Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited targets for chemotherapy. This study evaluated the inhibitory effects of novel imidazo[2,1-b]oxazole-based rapidly accelerated fibrosarcoma (RAF) inhibitors, KIST0215-1 and KIST0215-2, on epithelial cell transformation and TNBC tumorigenesis. MATERIALS AND METHODS: Immunoblotting, BrdU incorporation assay, reporter gene assay, and soft agar assay analyses were performed. In vivo effects were studied using the BALB/c mouse xenograft model. RESULTS: KIST0215-1 and KIST0215-2 inhibited the RAFs-MEK1/2-ERK1/2 signalling pathway induced by EGF in MDA-MB-231 cells, which inhibited c-fos transcriptional activity and activator protein-1 transactivation activity. KIST0215-1 and KIST0215-2 also prevented neoplastic transformation of JB6 C141 mouse epidermal cells induced by EGF and consistently suppressed the growth of tumours formed by 4T1 cells in BALB/c mice. CONCLUSION: Inhibition of RAF kinases using KIST0215-1 and KIST0215-2 is a promising chemotherapeutic strategy to treat TNBC.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Imidazóis/farmacologia , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Genes Reporter , Humanos , Imidazóis/química , Camundongos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Anticancer Res ; 40(9): 5091-5095, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878797

RESUMO

BACKGROUND/AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. RESULTS: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. CONCLUSION: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Survivina/genética , Taxoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Anticancer Res ; 40(9): 5107-5114, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878799

RESUMO

BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) via Sonic Hedgehog (Shh) signaling may be one of the mechanisms of progression of castration-resistant prostate cancer (CRPC). In this study, we investigated the possible therapeutic effect of vismodegib, a new Shh inhibitor, in a mouse CRPC model. MATERIALS AND METHODS: We determined cell proliferation, apoptosis and the expression of EMT-related genes for three prostate cancer cell lines; androgen-dependent LNCaP and independent C4-2B and PC-3 in the presence of vismodegib in vitro. Fifty mg/kg of vismodegib were orally administered into mice bearing C4-2B and PC-3 tumors, respectively every other week for 3 weeks. RESULTS: Vismodegib significantly inhibited cell proliferation and induced cell apoptosis in all cell lines in vitro (p<0.05). Vismodegib significantly inhibited EMT in CRPC cells and tumor growth in C4-2B-bearing mice compared to controls in vivo (p<0.05). Higher expression of caspase-3 and lower expression of vimentin in PC-3 and C4-2B tumors were induced by vismodegib in immunohistochemical analysis. CONCLUSION: Vismodegib inhibited cell proliferation via apoptosis and also suppressed EMT, showing anti-tumor effects in mice. Further mechanistic studies are needed to investigate the feasibility of vismodegib for CRPC treatment.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Proteínas Hedgehog/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Imunofenotipagem , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Anticancer Res ; 40(9): 5181-5189, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878806

RESUMO

BACKGROUND/AIM: Mathematical models have long been considered as important tools in cancer biology and therapy. Herein, we present an advanced non-linear mathematical model that can predict accurately the effect of an anticancer agent on the growth of a solid tumor. MATERIALS AND METHODS: Advanced non-linear mathematical optimization techniques and human-to-mouse experimental data were used to develop a tumor growth inhibition (TGI) estimation model. RESULTS: Using this mathematical model, we could accurately predict the tumor mass in a human-to-mouse pancreatic ductal adenocarcinoma (PDAC) xenograft under gemcitabine treatment up to five time periods (points) ahead of the last treatment. CONCLUSION: The ability of the identified TGI dynamic model to perform satisfactory short-term predictions of the tumor growth for up to five time periods ahead was investigated, evaluated and validated for the first time. Such a prediction model could not only assist the pre-clinical testing of putative anticancer agents, but also the early modification of a chemotherapy schedule towards increased efficacy.


Assuntos
Antineoplásicos/farmacologia , Modelos Teóricos , Dinâmica não Linear , Ensaios Antitumorais Modelo de Xenoenxerto , Algoritmos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
12.
Anticancer Res ; 40(9): 4869-4874, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878774

RESUMO

BACKGROUND/AIM: In the present study, we evaluated the efficacy of adjuvant administration of oral recombinant methioninase (o-rMETase) against recurrence and metastasis in a 4T1 murine breast-cancer syngeneic model. MATERIALS AND METHODS: 4T1 cells were orthotopically implanted into the 2nd mammary fat pad of BALB/c mice. The 4T1 orthotopic syngeneic models were randomized into 2 groups after primary tumor resection: untreated control and o-rMETase (100 units, oral, daily, 2 weeks). RESULTS: The frequency and extent of local recurrence were reduced by o-rMETase. The number of individual cancer cells and metastatic nodules on the lung surface was significantly lower in the o-rMETase-treated mice than the untreated control mice. CONCLUSION: Adjuvant o-rMETase inhibited local recurrence and lung metastasis after primary tumor resection.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Liases de Carbono-Enxofre/administração & dosagem , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Administração Oral , Animais , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Esquema de Medicação , Feminino , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/cirurgia , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Anticancer Res ; 40(9): 4947-4960, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878783

RESUMO

BACKGROUND/AIM: This study aimed to investigate the anticancer effects and potential mechanisms of sclareol in a human small cell lung carcinoma (SCLC) cell line. MATERIALS AND METHODS: Cell viability was determined by the MTT assay. Cell cycle, apoptosis and caspase activity were evaluated by flow cytometry. Cell cycle and DNA damage related protein expression was determined by western blotting. In vivo evaluation of sclareol was carried out in xenografted tumor mice models. RESULTS: Sclareol significantly reduced cell viability, induced G1 phase arrest and subsequently triggered apoptosis in H1688 cells. In addition, this sclareol-induced growth arrest was associated with DNA damage as indicated by phosphorylation of H2AX, activation of ATR and Chk1. Moreover, in vivo evaluation of sclareol showed that it could inhibit tumor weight and volume in a H1688 xenograft model. CONCLUSION: Sclareol might be a novel and effective therapeutic agent for the treatment of SCLC patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Diterpenos/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Anticancer Res ; 40(9): 4969-4978, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878785

RESUMO

BACKGROUND/AIM: Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis. RESULTS: The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05). CONCLUSION: BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brucea/química , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/patologia , Óleos Vegetais/uso terapêutico , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
PLoS One ; 15(9): e0238238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881880

RESUMO

The prognosis for patients with glioblastoma (GB) remains grim. Concurrent temozolomide (TMZ) radiation-the cornerstone of glioma control-extends the overall median survival of GB patients by only a few months over radiotherapy alone. While these survival gains could be partly attributed to radiosensitization, this benefit is greatly minimized in tumors expressing O6-methylguanine DNA methyltransferase (MGMT), which specifically reverses O6-methylguanine lesions. Theoretically, non-O6-methylguanine lesions (i.e., the N-methylpurine adducts), which represent up to 90% of TMZ-generated DNA adducts, could also contribute to radiosensitization. Unfortunately, at concentrations attainable in clinical practice, the alkylation capacity of TMZ cannot overwhelm the repair of N-methylpurine adducts to efficiently exploit these lesions. The current therapeutic application of TMZ therefore faces two main obstacles: (i) the stochastic presence of MGMT and (ii) a blunted radiosensitization potential at physiologic concentrations. To circumvent these limitations, we are developing a novel molecule called NEO212-a derivatization of TMZ generated by coupling TMZ to perillyl alcohol. Based on gas chromatography/mass spectrometry and high-performance liquid chromatography analyses, we determined that NEO212 had greater tumor cell uptake than TMZ. In mouse models, NEO212 was more efficient than TMZ at crossing the blood-brain barrier, preferentially accumulating in tumoral over normal brain tissue. Moreover, in vitro analyses with GB cell lines, including TMZ-resistant isogenic variants, revealed more potent cytotoxic and radiosensitizing activities for NEO212 at physiologic concentrations. Mechanistically, these advantages of NEO212 over TMZ could be attributed to its enhanced tumor uptake presumably leading to more extensive DNA alkylation at equivalent dosages which, ultimately, allows for N-methylpurine lesions to be better exploited for radiosensitization. This effect cannot be achieved with TMZ at clinically relevant concentrations and is independent of MGMT. Our findings establish NEO212 as a superior radiosensitizer and a potentially better alternative to TMZ for newly diagnosed GB patients, irrespective of their MGMT status.


Assuntos
Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Glioma/tratamento farmacológico , Radiossensibilizantes/uso terapêutico , Temozolomida/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dacarbazina/análise , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Cromatografia Gasosa-Espectrometria de Massas , Glioma/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Radiossensibilizantes/análise , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Temozolomida/análise , Temozolomida/metabolismo , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Nat Commun ; 11(1): 4684, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943635

RESUMO

Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy. We show that autophagy is essential for tumor cells to cope with therapeutic perturbation of metabolism and that mTORC1-mediated suppression of autophagy is required and sufficient for generating a metabolic vulnerability leading to energy crisis and apoptosis. Our study links mTOR-induced cancer drug resistance to autophagy defects as a cause of a metabolic liability and opens a therapeutic window for the treatment of otherwise therapy-refractory tumor patients.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose , Tratamento Farmacológico , Feminino , Humanos , Neoplasias Pulmonares , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Commun ; 11(1): 4660, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938908

RESUMO

Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Histona Desacetilase 1/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Humanos , Camundongos SCID , Fenilbutiratos/farmacologia , Transdução de Sinais , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Nat Commun ; 11(1): 4810, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968061

RESUMO

Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3-synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.


Assuntos
Basigina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Antígenos Quiméricos/efeitos dos fármacos , Animais , Basigina/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Células Matadoras Naturais , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
PLoS One ; 15(9): e0237981, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903271

RESUMO

Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicina Hidroximetiltransferase/metabolismo , Neoplasias Pulmonares/patologia , Metaboloma , Proteoma/análise , Serina/metabolismo , Animais , Antifúngicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Glicina Hidroximetiltransferase/antagonistas & inibidores , Glicina Hidroximetiltransferase/genética , Células HeLa , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Domínios e Motivos de Interação entre Proteínas , Benzoato de Sódio/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Anticancer Res ; 40(10): 5393-5397, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988858

RESUMO

BACKGROUND/AIM: We established a new patient-derived orthotopic xenograft (PDOX) model of gastric cancer liver metastasis and evaluated the efficacy of a novel combination chemotherapy, gemcitabine (GEM) plus 5-fluorouracil (5-FU), compared to a standard regimen of oxaliplatinum (L-OHP) plus 5-FU on the liver metastasis. MATERIALS AND METHODS: Patient-derived gastric cancer was established in nude mice from the patient' s surgical tumor specimen. A single tumor fragment was implanted in the liver of nude mice. The mice with tumors were treated by GEM plus 5-FU or L-OHP plus 5-FU. RESULTS: GEM plus 5-FU or L-OHP plus 5-FU significantly and similarly inhibited tumor growth on the liver compared to the untreated control (p=0.007, p=0.02, respectively). CONCLUSION: GEM plus 5-FU could be a novel future clinical alternative to L-OHP plus 5-FU in gastric cancer patients who cannot tolerate platinum drugs.


Assuntos
Desoxicitidina/análogos & derivados , Fluoruracila/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Oxaliplatina/farmacologia , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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