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1.
Nat Commun ; 12(1): 3414, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099731

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Lactamas Macrocíclicas/farmacologia , Neutrófilos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Neutrófilos/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
2.
Phytomedicine ; 86: 153563, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33951569

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Sorafenib (SORA), as a first-line therapeutic drug, has been used to treat HCC, but resistance poses a major limitation on the efficacy of SORA chemotherapy. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells in vitro. PURPOSE: The aim of this study was to investigate whether PRIS can exert synergistic anti-tumor effects with the combination of SORA, and if so, through what mechanism. METHODS: Conditionally reprogrammed patient derived-primary hepatocellular carcinoma cells (CRHCs) were isolated from human liver cancer tissues and treated with SORA and PRIS. Cell proliferation, apoptosis, migration and tube formation ability were detected by DNA content quantification, flow cytometry, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were assessed by qRT-PCR and Western blot respectively. RESULTS: Initially, we observed that the combination of the two drugs had a much stronger inhibitory effect on CRHCs growth than either drug alone. Moreover, the combination of 2 µM SORA and 1 µM PRIS exhibited a significant anti­migrative and anti-invaded effect on CRHCs, and remarkably inhibited capillary structure formation of Human Umbilical Vein Endothelial Cells (HUVECs). Furthermore, the combined treatment with SORA and PRIS synergistically induced intrinsic apoptosis in CRHCs, involving a caspase-4-dependent mechanism paralleled by an increased Bax/Bcl-xL ratio. These activities were mediated through ROS generation and the induction of endoplasmic reticulum (ER) stress and mitochondrial dysfunction. GRP78 silencing or ER stress inhibitor 4-phenylbutyric acid administration was revealed to abolish the anticancer effects of PRIS, indicating the critical role of GRP78 in mediating the bioactivity of PRIS. The present study also provides mechanistic evidence that PRIS modulated the Akt/FoxO1/p27kip1 signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and, consequently resulting in suppressed cell viability, migration and angiogenesis co-treated with SORA in CRHCs. CONCLUSION: Our results suggest the use of PRIS as sensitizers of chemotherapy paving the way for innovative and promising targeted chemotherapy-based therapeutic strategies in human HCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteína Forkhead Box O1/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Triterpenos Pentacíclicos/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/administração & dosagem , Células Tumorais Cultivadas
3.
Medicine (Baltimore) ; 100(18): e25579, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950935

RESUMO

RATIONALE: Until recently, the survival rate in patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) was approximately 30%. Tyrosine kinase inhibitors (TKIs), which are a new class of drugs that target BCR-ABL fusion protein, have shown to be effective in treating Ph+ ALL in adults. However, the resistance mechanisms that promote the disease recurrence have altered the initial success of these revolutionary agents. PATIENT CONCERNS: A 71-year-old Chinese female patient who suffered from severe shoulder and back pain for 1 week. DIAGNOSIS: The patient was diagnosed with Ph+ ALL (B-cell) because of the following items. Complete blood count showed extremely abnormal white blood cell count (26.26×109/l), hemoglobin concentration (65 g/l) and platelet count (14×109/l). And because that Bone marrow aspirate showed 72.5% lymphoblasts and 59.30% lymphoblasts were confirmed by flow cytometry (FCM). At mean time, Real-time fluorescent quantitative PCR analysis confirmed that the P190 BCR/ABL fusion gene expression was 5.9%. Karyotype analysis indicated the following: 45, XX, -7, t (922) (q34; q11) [cp3]. INTERVENTIONS: The patient was treated with chemotherapy and different TKIs including imatinib, dasatinib, ponatinib, and bosutinib. OUTCOMES: The patient achieved complete remissions with different TKIs after diagnose but relapsed afterward and died of infection. LESSONS: Multidrug-resistant mutations within the BCR-ABL1 kinase domain are an emerging clinical problem for patients receiving sequential TKIs therapy. Acquisition of E255K/V-inclusive mutations is usually associated with ponatinib resistance, thus it is necessary to screen out new real pan-inhibitor compounds for all BCR/ABL mutations and figure out the potential efficacy of asciminib-based drug combinations in the future.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Taxa de Mutação , Recidiva Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Análise Mutacional de DNA , Evolução Fatal , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Cariotipagem , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/farmacologia , Piridazinas/uso terapêutico
4.
Medicine (Baltimore) ; 100(18): e25690, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950949

RESUMO

OBJECTIVE: We conducted this study to evaluate the efficacy and safety of traditional Chinese medicine (TCM) in advanced non-small cell lung cancer (NSCLC) patients who underwent chemotherapy. DESIGN: This was a prospective, open-label, randomized controlled trial. NSCLC patients at stage IIIA, IIIB, or IV were randomly assigned to either TCM plus chemotherapy or chemotherapy alone. The comprehensive TCM treatment consisted of Kang Ai injection, herbal decoction, and Zhenqifuzheng capsules. The primary endpoint was quality of life (QOL) measured by the Functional Assessment of Cancer Therapy-Lung version 4.0. The secondary endpoints were chemotherapy completion rate, tumor response, and adverse events. All assessments were done at baseline, the third week, and the sixth week. RESULTS: Thirty-nine participants were randomly assigned to the treatment group and 36 to the control group. The QOL scores were significantly improved in the treatment group compared with those of the control group in social well-being (cycle 1, P = .048; cycle 2, P = .015), emotional well-being (cycle 1, P = .047; cycle 2, P = 4.29E-05), and functional well-being (cycle 1, P = .030; cycle 2, P = .003), while the QOL scores in the above 3 domains declined in the control group (P < .05). Both groups had a decline in the physical well-being score (cycle 1, P = .042; cycle 2, P = .017) and lung cancer symptom score (cycle 1, P = .001; cycle 2, P = .001) after 2 courses of intervention. The deterioration in physical well-being and lung cancer symptoms was noticeably smaller in the treatment group (P < .05). There were significant differences between the 2 groups in social well-being, emotional well-being, functional well-being, lung cancer symptom domain, and the total score (P < .05). Patients in the treatment group had a significantly lower incidence of platelet reduction than the control group (P = .028) after 2 cycles of treatment. No significant difference in nonhematological adverse events (AEs) was observed. CONCLUSION: This study illustrated that comprehensive TCM treatment could promote the QOL of NSCLC patients, alleviate symptoms, and reduce the AEs caused by chemotherapy, verifying the synergistic and attenuating effects of TCM in NSCLC patients undergoing chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (www.chictr.org.cn): ChiCTR-TRC-13003637.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Qualidade de Vida , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Incidência , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Contagem de Plaquetas , Estudos Prospectivos , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Trombocitopenia/prevenção & controle , Adulto Jovem
5.
Medicine (Baltimore) ; 100(18): e25784, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950974

RESUMO

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM). The response rate and the depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse. PATIENT CONCERNS: Two patients with multiple myeloma (MM) were selected to enroll in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113) because they did not have the good effect after traditional treatment. One is a 48-year-old male patient who received a diagnosis of IgG lambda MM in June 2015, he has received 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a complete response (CR). Approximately 11 months later, the disease progressed. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles); the response was poor, and the disease kept progressing. Another 65-year-old female patient received a diagnosis of IgG lambda MM in September 2016, she has received induction therapy with 1 cycle of bortezomib and dexamethasone (VD) and 4 cycles of lenalidomide and dexamethasone, the response was poor. DIAGNOSIS: Both patients were diagnosed with RRMM according to the International Myeloma Working Group criteria. INTERVENTIONS: Both patients received infusions of anti-BCMA CAR-T cells following an induction chemotherapy regimen of cyclophosphamide and fludarabine. OUTCOMES: Both of them achieved a stringent CR at the 30th day with minimal residual disease-negative bone marrow by flow cytometry and serum monoclonal protein was undetectable at 4 and 10 months after cell transfusion. The CR has persisted in the 2 patients for >36 months. CONCLUSIONS: Our findings demonstrate the anti-BCMA CAR-T cell treatment is a feasible therapeutic option for patients with RRMM. Fewer early lines of treatment may be beneficial to maintain the efficacy of CAR-T cells. TRIAL REGISTRATION: ChiCTR-OPC-16009113.


Assuntos
Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento
6.
Nat Commun ; 12(1): 2582, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976133

RESUMO

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/transplante , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/imunologia , Modelos Animais de Doenças , Feminino , Glioblastoma/imunologia , Humanos , /uso terapêutico , Memória Imunológica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
7.
Nat Commun ; 12(1): 2606, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972557

RESUMO

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Células Th17/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/imunologia , Sinergismo Farmacológico , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células Th17/imunologia , Proteína Supressora de Tumor p53/metabolismo
8.
Int J Mol Sci ; 22(5)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803402

RESUMO

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803480

RESUMO

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D3 metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24R)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)2D3 analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Anastrozol/agonistas , Anastrozol/farmacologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Calcitriol/análogos & derivados , Calcitriol/farmacologia , Di-Hidroxicolecalciferóis/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Anticancer Res ; 41(4): 1745-1751, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813378

RESUMO

BACKGROUND/AIM: Osteosarcoma is the most frequent malignant bone tumor. Failure of first-line therapy results in poor prognosis of osteosarcoma. In the present report, we examined the efficacy of the combination of oral recombinant methioninase (o-rMETase) and docetaxel (DOC) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: Osteosarcoma-PDOX models were established by tumor insertion within the tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups (4-5 mice per group): control; o-rMETae alone; DOC alone; o- rMETase combined with DOC. The treatment period was 3 weeks. RESULTS: The combination of o-rMETase and DOC showed significant efficacy compared to the control group (p=0.03). In contrast, there was no significant efficacy of o-rMETase alone or DOC alone (p=0.65, 0.60, respectively). CONCLUSION: o-rMETase converted an osteosarcoma PDOX from DOC-resistant to -sensitive. This combination therapy may be effective against recalcitrant osteosarcoma and other recalcitrant cancers.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Liases de Carbono-Enxofre/administração & dosagem , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Tíbia/efeitos dos fármacos , Administração Oral , Adolescente , Animais , Neoplasias Ósseas/patologia , Humanos , Masculino , Camundongos Nus , Osteossarcoma/patologia , Proteínas Recombinantes/administração & dosagem , Tíbia/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Anticancer Res ; 41(4): 1771-1778, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813381

RESUMO

BACKGROUND/AIM: Eicosapentaenoic acid (EPA) is an unsaturated fatty acid with various bioactivities, including antitumor effects. We previously reported a synergistic antitumor effect of cisplatin (CDDP) and EPA. Here, we examined the underlying mechanism. MATERIALS AND METHODS: The human oesophageal cancer cell line TE-1 was treated with the combination of EPA and CDDP. Nuclear translocation of NF-κB, a transcription factor involved in cytokine production, was detected by immunohistochemistry. IL-6 levels were measured by ELISA. Apoptosis and cell cycle distribution were evaluated by flow cytometry. RESULTS: Nuclear translocation of NF-κB in TE-1 cells was synergistically decreased by CDDP and EPA. IL-6 production was increased following treatment with CDDP, but treatment with EPA decreased IL-6 levels. Apoptosis was synergistically induced by CDDP and EPA. A G2/M cell cycle arrest was observed with the combination of CDDP and 150 µM EPA, and S phase arrest with the combination of CDDP and 100 µM EPA. CONCLUSION: The combination of CDDP and EPA synergistically suppresses NF-κB nuclear translocation and increases apoptosis by inducing cell cycle arrest at the S or G2/M phase.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Ácido Eicosapentaenoico/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais
12.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921230

RESUMO

Hepatocellular carcinoma (HCC) is a major histological subtype of primary liver cancer. Ample evidence suggests that the pathological properties of HCC originate from hepatic cancer stem cells (CSCs), which are responsible for carcinogenesis, recurrence, and drug resistance. Cold atmospheric-pressure plasma (CAP) and plasma-activated medium (PAM) induce apoptosis in cancer cells and represent novel and powerful anti-cancer agents. This study aimed to determine the anti-cancer effect of CAP and PAM in HCC cell lines with CSC characteristics. We showed that the air-based CAP and PAM selectively induced cell death in Hep3B and Huh7 cells with CSC characteristics, but not in the normal liver cell line, MIHA. We observed both caspase-dependent and -independent cell death in the PAM-treated HCC cell lines. Moreover, we determined whether combinatorial PAM therapy with various anti-cancer agents have an additive effect on cell death in Huh7. We found that PAM highly increased the efficacy of the chemotherapeutic agent, cisplatin, while enhanced the anti-cancer effect of doxorubicin and the targeted-therapy drugs, trametinib and sorafenib to a lesser extent. These findings support the application of CAP and PAM as anti-cancer agents to induce selective cell death in cancers containing CSCs, suggesting that the combinatorial use of PAM and some specific anti-cancer agents is complemented mechanistically.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Meios de Cultura/efeitos da radiação , Neoplasias Hepáticas/tratamento farmacológico , Gases em Plasma , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Meios de Cultura/farmacologia , Doxorrubicina/farmacologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação
13.
BMC Cancer ; 21(1): 358, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823836

RESUMO

BACKGROUND: A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle. METHODS: This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation. RESULTS: Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/µL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/µL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF. CONCLUSION: Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/µL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle. TRIAL REGISTRATION: UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neutropenia Febril/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/farmacologia , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab/farmacologia , Rituximab/uso terapêutico , Vincristina/farmacologia , Vincristina/uso terapêutico
14.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802664

RESUMO

Berberine (BBR) has been reported to have potent anticancer activity and can increase the anticancer effects of chemotherapy drugs. The present study aims to investigate whether BBR and cisplatin (DDP) exert synergistic effects on the osteosarcoma (OS) MG-63 cell line. In the present study, MG-63 cells were treated with BBR and DDP alone or in combination. The effects of these therapeutics on cell viability, colony formation, migration, invasion, nuclear morphology, apoptosis, and the cell cycle, as well as their role in regulating the expression of proteins related to apoptosis, the cell cycle, and the mitogen-activated protein kinase (MAPK) pathway, were determined. The results demonstrated that BBR or DDP significantly inhibited the proliferation of MG-63 cells in a dose- and time-dependent manner. The combination treatment of BBR and DDP exerted a prominent inhibitory effect on proliferation and colony formation. Furthermore, the results showed that the combination treatment of BBR and DDP enhanced the inhibition of cell migration and invasion and reversed the changes in nuclear morphology. The results showed that the combination treatment of BBR and DDP induced apoptosis and cell cycle arrest in the G0/G1 phase. Mechanistically, the combination treatment of BBR and DDP inhibited the expression of MMP-2/9, Bcl-2, CyclinD1, and CDK4, enhanced the expression of Bax and regulated the activity of the MAPK pathway. Collectively, our data suggest that the combination therapy of BBR and DDP markedly enhanced OS cell death.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Berberina/farmacologia , Cisplatino/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
15.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808494

RESUMO

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.


Assuntos
Glioblastoma/metabolismo , Glioma/metabolismo , Gossipol/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Gossipol/metabolismo , Gossipol/farmacologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Temozolomida/farmacologia , Microambiente Tumoral/efeitos dos fármacos
16.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803309

RESUMO

The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been approved for the breast cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival outcomes both in first and later line settings. The developments of the last five years in the search for new selective CDK4/6 inhibitors with increased selectivity, treatment efficacy, and reduced adverse effects are reviewed, considering the small-molecule inhibitors and proteolysis-targeting chimeras (PROTACs) approaches, mainly pointing at structure-activity relationships, selectivity against different kinases and antiproliferative activity.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Terapia de Alvo Molecular/tendências
17.
Cancer Invest ; 39(5): 369-378, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33886387

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy (ET) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER-2-) advanced breast cancer (ABC) patients. METHODS: We searched clinical trials of CDK4/6 inhibitors combined with ET and calculated the clinical outcomes. RESULTS: HR+/HER-2- ABC patients treated with CDK4/6 inhibitors combined with ET had significantly prolonged progression-free survival (PFS) and improved objective response rate (ORR) and clinical benefit rate (CBR). CONCLUSIONS: CDK4/6 inhibitors combined with ET can bring more clinical benefits to ABC patients, and the safety profile is acceptable.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Receptores de Estrogênio/uso terapêutico , Receptores de Progesterona/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos
18.
Nat Commun ; 12(1): 2383, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888713

RESUMO

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor ErbB-3/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , /uso terapêutico , Imunoterapia/métodos , Camundongos , Mutação , Medicina de Precisão/métodos , Receptor de Morte Celular Programada 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
BMC Cancer ; 21(1): 360, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827483

RESUMO

BACKGROUND: The rate of toxic deaths related to induction chemotherapy in the treatment of locally advanced head and neck cancers is unacceptable and calls into question this therapeutic strategy, which is however highly effective in terms of rate and speed of response. The purpose of the study was to investigate predictive factors of toxicity of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced head and neck cancers (LAHNC). METHODS: Between June 2009 and December 2017, 113 patients treated consecutively with TPF were included retrospectively. Patients were receiving induction chemotherapy for either an inoperable cancer or laryngeal preservation. For inoperable cancer, induction chemotherapy was proposed to patients presenting either a large tumor with strong symptoms (dyspnea, dysphagia, pain) or a tumor with rapid progression. Risk factors were chosen among the initial patient and tumour characteristics and chemotherapy modalities. RESULTS: Eighty-nine patients (79%) were male; the median age was 58 years [32-71]. Sixty-nine (61%) patients were treated for inoperable cancer and 44 (39%) for laryngeal preservation. 45% had stage IVa cancer, 28% stage III and 25% stage IVb. Sixty percent of patients had a partial response after TPF, 22% had a complete response, 12% were stable, 5% were progressing, and 1% had a discordant response. Thirty-four patients (30%) received enteral feeding during induction chemotherapy with TPF. The possibility of oral feeding without a tube was predictive of a better response (p = 0.003). Seven (6%) patients died during TPF. There was an increased risk of death with preexisting liver dysfunction (liver dysmorphia on imaging or decrease prothrombin rate) (p = 0.032). There was an increased risk of grade ≥ 3 infection if an enteral feeding occurred during the period of induction chemotherapy (p = 0.03). CONCLUSIONS: TPF induction chemotherapy had an 82% objective response rate with 6% toxic deaths. Nutritional status and the presence of hepatic dysfunction are significant risk factors to be taken into account in therapeutic decisions.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quimioterapia de Indução/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Taxoides/farmacologia , Taxoides/uso terapêutico
20.
Phytomedicine ; 86: 153564, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33895649

RESUMO

BACKGROUND: The 3-deoxysappanchalcone (3-DSC), a chemical separated from Caesalpinia sappan L, has been substantiated to display anti-inflammatory, anti-influenza, and anti-allergy activities according to previous studies. However, the underlying mechanisms of action on esophageal cancer remain unknown. PURPOSE: The present research aims to survey the action mechanisms of 3-DSC in esophageal squamous cell carcinoma (ESCC) cells in vitro. METHODS: Evaluation of cytotoxicity was determined by MTT tetrazolium salt assay and soft agar assay. Cell cycle distribution, apoptosis induction, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), and multi-caspases activity were appreciated by Muse™ Cell Analyzer. The expressions of cell cycle- and apoptosis-related proteins were presented using Western blotting. RESULTS: 3-DSC blocked cell growth and colony formation ability in a concentration-dependent manner and invoked apoptosis, G2/M cell cycle arrest, ROS production, MMP depolarization, and multi-caspase activity. Furthermore, Western blotting results demonstrated that 3-DSC upregulated the expression of phospho (p)-c-jun NH2-terminal kinases (JNK), p-p38, cell cycle regulators, pro-apoptotic proteins, and endoplasmic reticulum (ER) stress-related proteins whereas downregulated the levels of anti-apoptotic proteins and cell cycle promoters. The effects of 3-DSC on ROS induction were counteracted by pretreatment with N-acetyl-L-cysteine (NAC). Also, our results indicated that p38 (SB203580) and JNK (SP600125) inhibitor slightly inhibited 3-DSC-induced apoptosis. These results showed that 3-DSC-related G2/M phase cell cycle arrest and apoptosis by JNK/p38 MAPK signaling pathway in ESCC cells were mediated by ROS. CONCLUSION: ROS generation by 3-DSC in cancer cells could be an attractive strategy for apoptosis of cancer cells by inducing cell cycle arrest, ER stress, MMP loss, multi-caspase activity, and JNK/p38 MAPK pathway. Our findings suggest that 3-DSC is a promising novel therapeutic candidate for both prevention and treatment of esophageal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Chalconas/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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