Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.486
Filtrar
1.
Recent Results Cancer Res ; 215: 231-252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605232

RESUMO

In only few years, circulating tumor DNA (ctDNA) in breast cancer has moved from purely fundamental research to nearby daily use for treatment selection and drug-resistance assessment. Indeed, technical advances and widespread use of next-generation sequencing or digital PCR allowed for detection of very low amount of tumor DNA in bloodstream. The use of ctDNA as liquid biopsy able either to monitor tumor burden under treatment or to overcome tumor heterogeneity and identify potential targetable drivers. Time has come to define how ctDNA can be implemented for early or metastatic breast cancer management. Data from retrospective analyses of prospective trials have recently highlighted the potential advantages but also the limitations of ctDNA, in particular for patients under endocrine therapy.


Assuntos
Neoplasias da Mama , DNA Tumoral Circulante , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia
2.
Anticancer Res ; 39(10): 5461-5471, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570440

RESUMO

BACKGROUND/AIM: Multidrug resistance (MDR) is often associated with overexpression of P-glycoprotein (ABCB1) in cancer cells. Apatinib is a novel Vascular endothelial growth factor receptor-TKI (VEGFR-TKI) which inhibits the function of ABCB1 in certain cancers. This study aimed to investigate the effect of apatinib on the reversal of paclitaxel (PTX) resistance in A549 lung cancer cells (A549/PTX) and related mechanisms. MATERIALS AND METHODS: A549/PTX cells were treated with apatinib alone, PTX alone, or PTX and apatinib. Cell viability was measured by the CCK8 assay. Apoptosis rate, cell-cycle arrest, Rhodamine efflux and reactive oxygen species (ROS) generation were determined by flow cytometry. The intracellular paclitaxel concentration was measured by ultra performance liquid chromatography (UPLC). Protein levels were analyzed by western blotting. RESULTS: A549/PTX cells had significant resistance to PTX and higher expression of ABCB1 compared to A549 cells. Apatinib increased the cytotoxicity of PTX, enhanced PTX-induced apoptosis and cycle arrest, and triggered intracellular ROS generation in A549/PTX cells. In addition, apatinib treatment increased the concentration of intracellular PTX in A549/PTX cells. Apatinib-PTX combination inhibited AKT and ERK pathways. CONCLUSION: Apatinib reverses the drug resistance to PTX in A549 PTX-resistant cells through inhibiting the function of ABCB1 and resumes anti-cancer effects.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Piridinas/farmacologia , Células A549 , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Anticancer Res ; 39(9): 4775-4779, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519578

RESUMO

BACKGROUND: Osteosarcoma is a recalcitrant disease treated with surgery and intensive chemotherapy as standard. The 5-year survival rate of patients with relapsed and lung metastatic osteosarcoma is as low as 20%. MATERIALS AND METHODS: A 16-year-old patient developed left distal femoral high-grade osteosarcoma and underwent cisplatinum-based neoadjuvant chemotherapy and surgery. From the resected tumor, a patient-derived orthotopic xenograft (PDOX) model was established in the femur of nude mice. PDOX models were randomized into the following groups: untreated control, or treatment with doxorubicin (3 mg/kg, i.p., weekly for 14 days), sunitinib (40 mg/kg, oral gavage, daily for 14 days), pazopanib (100 mg/kg, oral gavage, daily for 14 days), temozolomide(25 mg/kg, oral gavage, daily for 14 days), and eribulin (1.5 mg/kg, i.p., daily for 14 days). Tumor volume and body weight were monitored twice a week. RESULTS: The osteosarcoma PDOX was resistant to doxorubicin, sunitinib, and pazopanib. In contrast, eribulin and temozolomide arrested tumor growth. CONCLUSION: This study demonstrated the utility of the PDOX model in allowing effective from non-effective drugs to be distinguished in a model in which the tumor was growing on the organ corresponding to that of the patient.


Assuntos
Cisplatino/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Adolescente , Animais , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Osteossarcoma/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int J Nanomedicine ; 14: 4503-4515, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417255

RESUMO

Purpose: Drug resistance is a major challenge for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment of lung cancer. Ferumoxytol (FMT) drives macrophage (MΦ) transformation towards a M1-like phenotype and thereby inhibits tumor growth. CpG oligodeoxynucleotide 2395 (CpG), a toll-like receptor 9 (TLR9) agonist, is an effective therapeutic agent to induce anticancer immune responses. Herein, the effect of co-administered FMT and CpG on MΦ activation for treating non-small cell lung cancer (NSCLC) was explored. Methods: The mRNA expression levels of M1-like genes in RAW 264.7 MΦ cells stimulated by FMT, CpG and FMT and CpG (FMT/CpG) were evaluated by quantitative reverse transcription PCR (qRT-PCR). Then, the effects of FMT/CpG-pretreated MΦ supernatant on apoptosis and proliferation of H1975 cells were detected by flow cytometry, and the expression of EGFR and its downstream signaling pathway in H1975 cells were explored by western blotting. Finally, a H1975 cell xenograft mouse model was used to study the anti-tumor effect of the combination of FMT and CpG in vivo. Results: FMT and CpG synergistically enhanced M1-like gene expression in MΦ, including tumor necrosis factor-α, interleukin (IL)-12, IL-1α, IL-1ß, IL-6 and inducible nitric oxide synthase (iNOS). FMT/CpG-pretreated MΦ supernatant inhibited proliferation and induced apoptosis of H1975 cells, accompanied by down-regulation of cell cycle-associated proteins and up-regulation of apoptosis-related proteins. Further studies indicated that the FMT/CpG-pretreated MΦ supernatant suppressed p-EGFR and its downstream AKT/mammalian target of rapamycin signaling pathway in H1975 cells. Furthermore, FMT/CpG suppressed tumor growth in mice accompanied by a decline in the EGFR-positive tumor cell fraction and increased M1 phenotype macrophage infiltration. Conclusion: FMT acted synergistically with CpG to activate MΦ for suppressed proliferation and promoted apoptosis of NSCLC cells via EGFR signaling. Thus, combining FMT and CpG is an effective strategy for the treatment of NSCLC with EGFRL858R/T790M mutation.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Óxido Ferroso-Férrico/uso terapêutico , Macrófagos/metabolismo , Mutação/genética , Oligodesoxirribonucleotídeos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/genética , Feminino , Óxido Ferroso-Férrico/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Life Sci ; 233: 116709, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369760

RESUMO

BACKGROUND: Cisplatin resistance has been found to contribute to the failure of ovarian carcinoma treatment. Oridonin is a natural en-kaurane tetracyclic diterpenoid compound discovered in Rabdosia rubescene (Henmsl.) Hara. Herein, we tested whether oridonin could exert chemo-sensitization activity on cisplatin-resistant ovarian carcinoma cells. METHODS: Firstly, A2780CP cells and SKOV3/DDP cells were exposed to cisplatin and/or oridonin treatment. Cell counting kit-8 (CCK-8) kit and Dead Cell Apoptosis Kit with Annexin V-FITC and PI were carried out to test cell viability and apoptosis, respectively. Then, pBeclin-1 was transfected to overexpress Beclin-1. 3-Methyladenine (3-MA) acted as autophagy inhibitor, while rapamycin acted as autophagy activator. Finally, the influence of cisplatin and/or oridonin treatment on human normal ovarian epithelial IOSE 364 cell viability and apoptosis were also detected. RESULTS: Oridonin incubation notably elevated the cisplatin-caused reduction of A2780CP and SKOV3/DDP cell viabilities and enhancement of cell apoptosis. Cisplatin-caused A2780CP and SKOV3/DDP cell autophagy was dramatically inhibited by oridonin. Overexpression of Beclin-1 mitigated the influence of oridonin on cisplatin-caused A2780CP and SKOV3/DDP cell autophagy. Inhibition of cell autophagy by 3-MA promoted the oridonin + cisplatin-caused A2780CP and SKOV3/DDP cell apoptosis, while activation of cell autophagy by rapamycin had opposite effects. Oridonin and cisplatin co-treatment had no significant effects on IOSE 364 cell viability and apoptosis. CONCLUSION: The chemo-sensitization activity of oridonin on cisplatin-resistant ovarian carcinoma cells was verified in this study. Oridonin elevated sensitivity of ovarian carcinoma cells to cisplatin via suppressing cisplatin-mediated autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Cisplatino/farmacologia , Diterpenos de Caurano/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Neoplasias Ovarianas/patologia , Antineoplásicos/farmacologia , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas
7.
Cancer Sci ; 110(10): 3275-3287, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368616

RESUMO

p97/VCP is an endoplasmic reticulum (ER)-associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER-associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell-based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC50 , 100-500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib-resistant cell line and primary myeloma cells purified from patients. Accumulation of poly-ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly-ubiquitinated protein. IC50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1-0.8 µmol/L) than those of DBeQ (2-5 µmol/L). In silico protein-drug-binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell-free ATPase assays, OSSL_325096 showed dose-dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti-myeloma activity, at least in part through p97/VCP inhibition.


Assuntos
Adenosina Trifosfatases/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Inibidores Enzimáticos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/química , Animais , Sítios de Ligação , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos , Modelos Moleculares , Mieloma Múltiplo/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Proteínas Serina-Treonina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fator de Transcrição CHOP/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto , eIF-2 Quinase/metabolismo
8.
Cancer Sci ; 110(10): 3215-3224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432603

RESUMO

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Pelados , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Eur J Med Chem ; 179: 849-862, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302589

RESUMO

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Dicetopiperazinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Dicetopiperazinas/química , Dicetopiperazinas/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Anticancer Res ; 39(7): 3711-3718, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262897

RESUMO

BACKGROUND/AIM: Small cell lung cancer (SCLC) originates from neuroendocrine branchial cells (15-20%). It is regarded as distinct from other lung cancers due to its biological and clinical features. In most cases of SCLC, surgery or radiotherapy alone is not an effective cure. The aim of our study was to examine the cytotoxic effects of chemotherapy supported by electroporation (EP) on a resistant SCLC model, in vitro. MATERIAL AND METHODS: The multidrug resistant small lung cell line H69AR was used to evaluate the cytotoxic effects of cisplatin (CPPD) and vinorelbine (Navirel®; NAV) at lower doses when used with EP. Cells were treated with different concentrations of CPPD and NAV, alone or in combination with the following EP parameters: 400-1200 V/cm, 8 pulses of 100 µs duration, at 1Hz. The cell viability was estimated by MTT assay after 24 and 48 h. Apoptotic cells were detected by neutral comet assay and immunofluorescence assay with PARP-6. RESULTS: CPPD and NAV alone showed a dose-dependent effect on cell viability. Cytostatic drugs combined with EP revealed increased anticancer activity. Lower doses of CPPD or NAV delivered by EP were as effective as higher doses of these drugs without EP. The electrochemotherapeutic protocols increased the number of apoptotic cells and increased immunoreactivity of PARP-6. Our results indicated higher sensitivity of H69AR cells to NAV supported by EP. CONCLUSION: In SCLC cells, an increased anticancer activity was potentiated by exposure of cells to high intensity electric pulses and low drug doses. It is suggested that this method could be effectively applied in the treatment of lung cancer.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Eletroquimioterapia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Vinorelbina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos
11.
Eur J Med Chem ; 179: 358-375, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260890

RESUMO

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 µM and 10.71 µM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Células A549 , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/química , Relação Estrutura-Atividade
13.
Cancer Sci ; 110(9): 2884-2893, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31265163

RESUMO

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Acrilamidas/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Exantema/induzido quimicamente , Exantema/epidemiologia , Humanos , Japão/epidemiologia , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Paroniquia/induzido quimicamente , Paroniquia/epidemiologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Análise de Sobrevida , Taxa de Sobrevida
14.
J Cancer Res Clin Oncol ; 145(9): 2357-2363, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273511

RESUMO

BACKGROUND: Hepatic arterial infusion (HAI) of chemotherapy could be used in patients with liver-only metastatic colorectal cancer (mCRC) to fight against chemoresistance. We previously reported the efficacy of raltitrexed plus oxaliplatin (HAI) in a retrospective series. We performed a randomized two-stage phase-II study to evaluate the efficacy of HAI of the combination of raltitrexed and oxaliplatin in refractory mCRC with only liver metastases in comparison with standard of care. PATIENTS AND METHODS: Eligible patients had unresectable mCRC and were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were randomized between HAI raltitrexed (3 mg/m2 over 1 h) followed by oxaliplatin (130 mg/m2 over 2 h) every 3 weeks and standard of care in a 2:1 ratio. A total of 57 patients (38 in the experimental arm and 19 in the standard of care arm) were to be included. The main objective was to demonstrate 6-month PFS of 45% by intention-to-treat analysis in the experimental arm, compared to theoretical PFS of 20%, with a unilateral alpha risk of 5% and beta risk of 10%. RESULTS: After inclusion of 27 patients, the trial was terminated due to insufficient accrual. In the experimental arm, 11 and 4 patients experienced grade 3 and 4 toxicities, respectively. The most frequent grade 3-4 toxicities were neutropenia, liver toxicity, and abdominal pain. Median progression-free survival was 6.7 months (95% Confidence Interval; 3.9-7.2) in the HAI group and 2.2 months (95% CI 1.2-4.3) with standard of care [HR 0.32 (95% CI 0.14-0.76), p = 0.01]. Median overall survival did not differ between the two groups, at 11.2 months (95% CI 4.8-17.6) for the HAI group and 11.9 months (95% CI 2.8-14.3) for standard of care [HR 0.86 (95% CI 0.36-2.04), p = 0.73]. CONCLUSION: Although stopped prematurely, this randomized trial provides evidence for the benefit and safety of HAI of a combination of raltitrexed and oxaliplatin in liver-only mCRC with chemoresistant disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Oxaliplatina/administração & dosagem , Quinazolinas/administração & dosagem , Tiofenos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , França , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Quinazolinas/efeitos adversos , Padrão de Cuidado , Tiofenos/efeitos adversos , Resultado do Tratamento
15.
Anticancer Res ; 39(7): 3571-3578, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262881

RESUMO

BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cancer-selective, cell-death-inducing agent with little toxicity to normal cells. However, various human cancers and cancer cell lines have been reported to be resistant to TRAIL. Molecular clarification of resistance mechanism is needed. MATERIALS AND METHODS: Compound screening, proliferation assays, western blotting, and flow cytometry were used to examine the sensitizer activity of methyl transferase inhibitor BIX-01294 in combination with TRAIL, in hepatocellular carcinoma (HCC) cells. RNA sequencing analysis and single guide (sg)RNA-mediated gene deletion were used to investigate the role of survivin in sensitization. RESULTS: In HCC cells, BIX-01294 enhanced TRAIL sensitivity by reducing survivin expression at the RNA level. Small interference RNA-mediated gene knockdown demonstrated the mechanism of sensitization to be via the reduction of survivin. CONCLUSION: Euchromatin histone methyltransferase 2 (EHMT2) inhibition by BIX-01294 may be a potent anti-tumor therapeutic strategy for human HCC.


Assuntos
Azepinas/farmacologia , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quinazolinas/farmacologia , Survivina/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Survivina/genética
16.
Anticancer Res ; 39(7): 3585-3593, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262883

RESUMO

BACKGROUND: The oncogenic role of epidermal growth factor receptor (EGFR) has been intensively studied. However, its emerging role in drug resistance has not been fully addressed. MATERIALS AND METHODS: This study systematically investigated the correlation of mRNA and protein expression of EGFR, as well as gene amplification and mutations with the log-transformed half-maximal inhibitory concentration (log10IC50) values obtained from the NCI panel of 60 human tumor cell lines against 83 standard anticancer agents and the top 10 natural cytotoxic products previously screened by us. RESULTS: EGFR protein expression, rather than other measurements, was most frequently associated with drug response. Log10IC50 and EGFR protein level were significantly positively correlated under all investigated DNA topoisomerase (TOPO) II inhibitors, followed by 81% of alkylating agents and platinum-based compounds, 71% of anti-hormones, 66% of TOPO I inhibitors and 50% of antibiotics. Furthermore, 60% of cytotoxic natural products did not reveal significant correlations. CONCLUSION: Collectively, we showed a broad-spectrum of cross-resistance towards clinical drugs mediated by EGFR. Natural cytotoxic products may be further developed as novel drugs to overcome EGFR-associated resistance to clinically established anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/fisiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , RNA Mensageiro/metabolismo
17.
Anticancer Res ; 39(7): 3757-3765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262902

RESUMO

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. MATERIALS AND METHODS: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.


Assuntos
Antimitóticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , Cetonas/farmacologia , Lopinavir/farmacologia , Nelfinavir/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Flufenazina/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Ritonavir/farmacologia
18.
Anticancer Res ; 39(7): 3767-3775, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262903

RESUMO

BACKGROUND/AIM: Previously, we showed that KBV20C cancer cells highly resistant to antimitotic drugs were sensitized by co-treatment with a repositioned drug fluphenazine. MATERIALS AND METHODS: Considering that fluphenazine plays a role as a histamine receptor antagonist, we investigated low doses of 21 other histamine receptor antagonists (lidocaine, cimetidine, chlorpromazine, diphenhydramine, promethazine, ranitidine, famotidine, clemastine, chlorpheniramine, desloratadine, loratadine, cyproheptadine, azelastine, brompheniramine, carbinoxamine, fexofenadine, hydroxyzine, levocetirizine, meclizine, nizatidine, and pemirolast) to identify repositioned drugs for their sensitizing effects on antimitotic drug-resistant KBV20C cells at relatively low doses. RESULTS: Co-treatment with loratadine, and with azelastine highly sensitized KBV20C cells to vincristine treatment. Loratadine and azelastine reduced cell viability, increased G2 arrest, and up-regulated apoptosis when co-administered with vincristine. In detailed quantitative analysis, combination of vincristine with loratadine had a higher sensitization effect than that with azelastine. Azelastine had a higher P-glycoprotein (P-gp)-inhibitory activity, similar to that of verapamil, indicating that sensitization by vincristine-azelastine involved the P-gp-inhibitory effects of azelastine. However, loratadine had a very low P-gp-inhibitory activity, suggesting that loratadine sensitization to vincristine is independent of the P-gp-inhibition. Co-treatment with eribulin and loratadine increased the sensitization of KBV20C cells, suggesting that loratadine can be combined with other antimitotic drugs to sensitize resistant cancer cells. CONCLUSION: These findings provide important information regarding the sensitization of drug-resistant cells and indicate that loratadine may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antimitóticos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Loratadina/farmacologia , Ftalazinas/farmacologia , Vincristina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos
19.
Anticancer Res ; 39(7): 3777-3783, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262904

RESUMO

BACKGROUND/AIM: Selenium-containing compounds are becoming new alternatives in experimental chemotherapy in order to overcome multidrug resistance in cancer. The main goal of this study was to determine whether combined treatment with new Se-compounds would increase the effect of conventional doxorubicin chemotherapy in breast cancer cell lines. MATERIALS AND METHODS: Se-compounds were evaluated regarding their cytotoxic and apoptosis-inducing effect on MCF-7 and ATP-binding cassette subfamily B member 1 (ABCB1)-overexpressing KCR breast cancer cell lines. Moreover, the interaction of Se-compounds with doxorubicin was assessed using the MTT assay. RESULTS: Selenoanhydride exerted a selective activity towards the doxorubicin-resistant KCR cell line overexpressing ABCB1. Among the selenoesters, only ketone-containing selenoesters exerted significant cytotoxic activity against MCF-7 and KCR cell lines and the Se-compounds acted synergistically with doxorubicin on the KCR cell line. CONCLUSION: The importance of the COSeCH2COCH3 and COSeCH2CO(CH3)3 moieties for the cytotoxic and adjuvant role of Se-compounds was highlighted.


Assuntos
Anidridos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Compostos de Selênio/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Humanos
20.
Anticancer Res ; 39(7): 3785-3793, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262905

RESUMO

BACKGROUND/AIM: This study investigated drugs able to sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to vincristine or eribulin treatment and assessed their associated mechanisms of action. MATERIALS AND METHODS: Eight tyrosine kinase inhibitors (lapatinib, gefitinib, imatinib, erlotinib, nilotinib, pazopanib, cediranib, and vandetanib) and one serine/threonine kinase inhibitor (selumetinib) were evaluated for their sensitizing effects on vincristine-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were further performed to investigate their mechanisms of action. RESULTS: Co-treatment of KBV20C cells with lapatinib, gefitinib, imatinib, or erlotinib at low doses highly sensitized them to vincristine treatment. These drugs reduced cellular viability, increased G2 arrest, and up-regulated apoptosis when co-administered with vincristine. In a detailed quantitative analysis using lower doses, we demonstrated that lapatinib, with high P-gp inhibitory activity, yielded the best pairing for sensitizing P-gp-overexpressing KBV20C cells to vincristine. Co-treatment with eribulin and lapatinib, gefitinib, or erlotinib also increased the sensitivity of KBV20C cells, suggesting that they can be combined with other antimitotic drugs to sensitize resistant cancer cells. Lapatinib was shown to have a higher P-gp-inhibitory activity than verapamil, even at lower doses, indicating that its sensitizing of cells to vincristine involves its P-gp-inhibitory effects. However, interestingly, imatinib- and erlotinib-sensitizing of cells to vincristine appears to be independent of their P-gp inhibition. CONCLUSION: These findings provide valuable information regarding the sensitizing of drug-resistant cells and indicate that imatinib and erlotinib may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.


Assuntos
Antimitóticos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Gefitinibe/farmacologia , Humanos , Lapatinib/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA