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1.
J Cancer Res Clin Oncol ; 145(10): 2507-2517, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485766

RESUMO

BACKGROUND: Autophagy plays an important role in regulating cisplatin (CDDP) resistance in gastric cancer cells. However, the underlying mechanism of methioninase (METase) in the regulation of autophagy and CDDP resistance of gastric cancer cells is still not clear. MATERIALS AND METHODS: Western blot was used to detect the levels of autophagy-related proteins, multidrug-resistant 1 (MDR-1), and FoxM1 protein. LncRNA HULC was detected by qRT-PCR. Cell viability was detected using CCK-8 assay. The interaction between lncRNA HULC and FoxM1 was confirmed by RNA pull-down and RIP assay. RESULTS: Lentiviral vector carrying METase (LV-METase) suppressed autophagy and CDDP resistance of drug-resistant gastric cancer cells. LncRNA HULC was significantly downregulated in drug-resistant gastric cancer cells transfected with LV-METase. Besides, we found that lncRNA HULC interacted with FoxM1. In addition, METase suppressed autophagy to reduce CDDP resistance of drug-resistant gastric cancer cells through regulating HULC/FoxM1, and interfering HULC suppressed autophagy to reduce CDDP resistance of drug-resistant gastric cancer cells through regulating FoxM1. Finally, interfering HULC inhibited tumor growth in vivo. CONCLUSION: METase suppressed autophagy to reduce CDDP resistance of drug-resistant gastric cancer cells through regulating HULC/FoxM1 pathway.


Assuntos
Autofagia/efeitos dos fármacos , Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Forkhead Box M1/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Cisplatino/farmacologia , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Ligação Proteica , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Phys Chem Chem Phys ; 21(37): 20951-20964, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31524891

RESUMO

As a promising drug target in the treatment of lung cancer, anaplastic lymphoma kinase (ALK) and its mutations have been studied widely through the development of multiple generations of inhibitors. Experiments have found that compared with the wild-type, the L1198F and C1156Y/L1198F mutations resulted in resistance to 5P8 inhibitors, and the C1156Y mutation resulted in resistance to VGH inhibitors. In this study, the newly developed interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field was utilized to explore the origin of the resistance mechanism of the ALK mutant system. The calculated binding free energy was consistent with the experimental results. Per-residue binding free energy decomposition showed that the predicted hot-spot residues (LEU1122, LEU/PHE1198, MET1199, GLY1202 and LEU1256) were almost identical across systems. Especially, the GLU1197 residue played an important role in inducing drug-resistance for both inhibitors. The electrostatic interaction of GLU1197, PHE1198 and MET1199 mainly resulted in the resistances of the L1198F and C1156Y/L1198F mutations to 5P8. And the van der Waals interaction energy of LEU1256 residue, and electrostatic energy and entropy change of GLU1197 resulted in the resistances of the C1156Y mutations to VGH. The indicated origins of the drug-resistance in the ALK systems provide a theoretical foundation for the design of potent inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Entropia , Mutação/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Eletricidade Estática
3.
Anticancer Res ; 39(9): 4817-4828, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519584

RESUMO

BACKGROUND/AIM: Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. MATERIALS AND METHODS: YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. RESULTS: Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. CONCLUSION: Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Survivina/genética , Tiofenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Masculino , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Adv Exp Med Biol ; 1152: 229-241, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456186

RESUMO

A large proportion of breast cancer patients are estrogen receptor positive. They generally benefit from tamoxifen, the drug that targets estrogen receptor signaling. However, de novo and acquired resistance against tamoxifen is well known. A number of signaling pathways and de-regulated factors have been evaluated to better understand the mechanism(s) of tamoxifen resistance. For past several years, non-coding RNAs have also gained attention as the putative regulators and determinants of tamoxifen resistance. A number of reports have documented evidence from in vitro and/or in vivo studies, as well as from evaluation of clinical samples, to showcase the power of non-coding RNAs as mediators of tamoxifen resistance and the predictors of disease relapse. This article puts into perspective the available information on microRNAs and the long non-coding RNAs regarding their ability to tweak resistance vs. sensitivity to tamoxifen.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos
5.
Anticancer Res ; 39(8): 4023-4030, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366484

RESUMO

BACKGROUND: Treatment options for patients with platinum-resistant ovarian cancer are generally palliative in nature and rarely have realistic potential to be curative. Because many patients with recurrent ovarian cancer receive aggressive chemotherapy for prolonged periods, sometimes continuously, therapy-related toxicities are a major factor in treatment decisions. The use of ex vivo drug sensitivity screens has the potential to improve the treatment of patients with platinum-resistant ovarian cancer by providing personalized treatment plans and thus reducing toxicity from unproductive therapy attempts. MATERIALS AND METHODS: We evaluated the treatment responses of a set of six early-passage patient-derived ovarian cancer cell lines towards a set of 30 Food and Drug Administration-approved chemotherapy drugs using drug-sensitivity testing. RESULTS: We observed a wide range of treatment responses of the cell lines. While most compounds displayed vastly different treatment responses between cell lines, we found that some compounds such as docetaxel and cephalomannine reduced cell survival of all cell lines. CONCLUSION: We propose that ex vivo drug-sensitivity screening holds the potential to greatly improve patient outcomes, especially in a population where multiple continuous treatments are not an option due to advanced disease, rapid disease progression, age or poor overall health. This approach may also be useful to identify potential novel therapeutics for patients with ovarian cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Platina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Platina/efeitos adversos
6.
Anticancer Res ; 39(8): 4031-4041, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366485

RESUMO

BACKGROUND/AIM: Eribulin is currently used to treat advanced and metastatic breast cancer in the clinical setting; however, its efficacy is inhibited by resistance acquisition in many cases. Thus, the present study established two eribulin-resistant breast-cancer cell lines, and used these to investigate the mechanisms that underly eribulin-resistance acquisition. MATERIALS AND METHODS: Eribulin-resistant breast-cancer cell lines were generated by culturing MDA-MB-231 and MCF-7 cells with increasing concentrations of eribulin. RESULTS: The eribulin-resistant cells acquired resistance to eribulin, as well as several other anticancer drugs. After eribulin treatment, the eribulin-resistant cell lines showed no morphological change, no increased expression of epithelial-cadherin, nor any significant alteration in cell-cycle distribution. In contrast, the expression levels of programmed death-ligand 1 were increased in the MCF-7/eribulin-resistant compared to MCF-7 cells. CONCLUSION: The herein developed eribulin-resistant cell lines acquired cross-resistance to various anticancer agents, and displayed resistance to eribulin-induced effects on microtubule function and epithelial-mesenchymal transition (EMT).


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Furanos/administração & dosagem , Cetonas/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Células MCF-7 , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Anticancer Res ; 39(8): 4079-4084, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366491

RESUMO

BACKGROUND/AIM: Recurrent osteosarcoma is a recalcitrant disease; therefore, an improved strategy is urgently needed to provide therapy. In order to develop a novel strategy for this disease, our lab has developed a patient-derived orthotopic xenograft (PDOX) mouse model for osteosarcoma. The combination of sorafenib (SFN) and palbociclib (PAL) was shown to be effective of hepatocellular carcinoma. However, whether this combination is efficacious on osteosarcoma has not been reported. The aim of this study was to determine the efficacy of the SFN and PAL combination on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into five treatment groups: untreated-control, CDDP, SFN, PAL and the combination of SFN and PAL. RESULTS: Of these agents, the SFN-PAL combination significantly regressed tumor growth, and enhanced tumor necrosis with degenerative changes in the osteosarcoma PDOX. CONCLUSION: The SFN-PAL combination is an effective treatment strategy for osteosarcoma and therefore holds promise for clinical efficacy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Osteossarcoma/tratamento farmacológico , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Sorafenibe/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Humanos , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Anticancer Res ; 39(8): 4101-4110, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366494

RESUMO

BACKGROUND/AIM: Despite improvements in cancer therapy, life expectancy after tumor recurrence remains low. Relapsed cancer is characterized by drug resistance, often mediated through overexpression of multidrug resistance (MDR) genes. Camellia sinensis non fermentatum extract is known for its anticancer properties in several cancer cell lines and might improve cancer therapy outcome after tumor recurrence. MATERIALS AND METHODS: Embryonal rhabdomyosarcoma cell lines, alveolar rhabdomyosarcoma cell lines and primary rhabdomyosarcoma MAST139 cells were used to test NPE® effects on cell viability in combination with chemotherapeutic agents. Cell viability was measured by the WST-1 assay and CV staining. Gene expression levels of chemotherapy-induced efflux pumps and their activity was assessed upon NPE® treatment by measuring doxorubicin retention through evaluation of the autofluorescence signal. RESULTS: Administration of increasing doxorubicin concentrations triggered immediate adaptation to the drug, which was surprisingly overcome by the addition of NPE®. Investigating the mechanism of immediate adaptation, MDR1 gene overexpression was observed upon doxorubicin treatment. Although NPE® did not alter pump gene expression, it was able to reduce pump activity, thus allowing the chemotherapeutic agent to stay inside the cells to exert its full anticancer activity. CONCLUSION: NPE® might improve chemotherapeutic treatment by re-sensitizing relapsed tumors to anticancer drugs. Fighting MDR represents the key to overcome tumor relapse and improve the overall survival of cancer patients.


Assuntos
Antineoplásicos/farmacologia , Camellia sinensis/química , Recidiva Local de Neoplasia/tratamento farmacológico , Rabdomiossarcoma Alveolar/tratamento farmacológico , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Rabdomiossarcoma Alveolar/patologia
9.
Anticancer Res ; 39(8): 4129-4136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366497

RESUMO

BACKGROUND/AIM: 5-Aza-2-deoxycytidine (5-Aza-CdR) enhances the sensitivity to 5-fluorouracil (5-FU), but the molecular mechanism is not fully understood. The aim of this study was to investigate the molecular mechanism that enhances the sensitivity to 5-FU treated with 5-Aza-CdR via thymidine phosphorylase (TP). MATERIALS AND METHODS: The sensitivity to drugs was determined on several cancer cell lines by the MTT assay. Protein and mRNA levels were examined by immunoblot and RT-PCR, respectively. Gene silencing, binding of Sp1 to DNA and methylation of DNA was performed by siRNA, ChIP assay and sodium bisulfate genomic sequencing, respectively. RESULTS: Sp1-binding sites in the TP promoter were methylated in epidermoid carcinoma. 5-Aza-CdR demethylated Sp1-binding sites and enhanced sensitivity to 5-FU. CONCLUSION: Demethylation of Sp1-binding sites by 5-Aza-CdR was a key factor enhancing 5-FU sensitivity, which may enable more effective treatments for cancer patients with the combination of 5-Aza-CdR and 5-FU.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição Sp1/genética , Timidina Fosforilase/genética , Sítios de Ligação/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Decitabina/metabolismo , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/genética , Timidina Fosforilase/química
10.
Gene ; 714: 143972, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31301483

RESUMO

Among cancers, lung cancer is the most morbidity and mortality disease that is remaining the fatalist. Generally, there are multiple treatment procedures for lung cancer, such as surgery, immunotherapy, radiotherapy and chemotherapy. There is, therefore, an urgent need for more specified and efficient methods for treatment of lung cancer such as RNAi, which in combination with traditional therapies could silence genes that are involved in the drug resistance. These genes may either be motivators of apoptosis inhibition, EMT and DNA repair system promoters or a member of intracellular signaling pathways, such as JAK/STAT, RAS/RAF/MEK, PI3K/AKT, NICD, B-catenin/TCF/LEF and their stimulator receptors including IGFR, EGFR, FGFR, VEGFR, CXCR4, MET, INTEGRINS, NOTCH1 and FRIZZLED, so could be considered as appropriate targets. In current review, the results of multiple studies which have employed drug application after one specific gene silencing or more than one gene from distinct pathways also simultaneous drug and RNAi usage in vitro and in vivo in lung cancer were summarized.


Assuntos
Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , RNA Interferente Pequeno/genética , Animais , Apoptose/genética , Humanos , Transdução de Sinais/genética
11.
Adv Exp Med Biol ; 1143: 75-93, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338816

RESUMO

As the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), N 6-methyladenosine (m6A) modification has been shown recently to posttranscriptionally regulate expression of thousands of messenger RNA (mRNA) transcripts in each mammalian cell type in a dynamic and reversible manner. This epigenetic mark is deposited by the m6A methyltransferase complex (i.e., the METTL3/METTL14/WTAP complex and other cofactor proteins) and erased by m6A demethylases such as FTO and ALKBH5. Specific recognition of these m6A-modified mRNAs by m6A-binding proteins (i.e., m6A readers) determines the fate of target mRNAs through affecting splicing, nuclear export, RNA stability, and/or translation. During the past few years, m6A modification has been demonstrated to play a critical role in many major normal bioprocesses including self-renewal and differentiation of embryonic stem cells and hematopoietic stem cells, tissue development, circadian rhythm, heat shock or DNA damage response, and sex determination. Thus, it is not surprising that dysregulation of the m6A machinery is also closely associated with pathogenesis and drug response of both solid tumors and hematologic malignancies. In this chapter, we summarize and discuss recent findings regarding the biological functions and underlying mechanisms of m6A modification and the associated machinery in normal hematopoiesis and the initiation, progression, and drug response of acute myeloid leukemia (AML), a major subtype of leukemia usually associated with unfavorable prognosis.


Assuntos
Adenosina , Hematopoese , Leucemia Mieloide Aguda , Metiltransferases , RNA Mensageiro , Adenosina/metabolismo , Animais , Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos/genética , Hematopoese/genética , Humanos , Leucemia Mieloide Aguda/fisiopatologia , Metiltransferases/metabolismo , RNA Mensageiro/metabolismo
12.
J Cancer Res Clin Oncol ; 145(8): 1949-1976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292714

RESUMO

PURPOSE: Efflux transporters of the adenosine triphosphate-binding cassette (ABC)-superfamily play an important role in the development of multidrug resistance (multidrug resistant; MDR) in cancer. The overexpression of these transporters can directly contribute to the failure of chemotherapeutic drugs. Several in vitro and in vivo models exist to screen for the efficacy of chemotherapeutic drugs against MDR cancer, specifically facilitated by efflux transporters. RESULTS: This article reviews a range of efflux transporter-based MDR models used to test the efficacy of compounds to overcome MDR in cancer. These models are classified as either in vitro or in vivo and are further categorised as the most basic, conventional models or more complex and advanced systems. Each model's origin, advantages and limitations, as well as specific efflux transporter-based MDR applications are discussed. Accordingly, future modifications to existing models or new research approaches are suggested to develop prototypes that closely resemble the true nature of multidrug resistant cancer in the human body. CONCLUSIONS: It is evident from this review that a combination of both in vitro and in vivo preclinical models can provide a better understanding of cancer itself, than using a single model only. However, there is still a clear lack of progression of these models from basic research to high-throughput clinical practice.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos/isolamento & purificação , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Modelos Biológicos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Técnicas de Cultura/métodos , Técnicas de Apoio para a Decisão , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Especificidade de Órgãos , Seleção de Pacientes
13.
Zhonghua Zhong Liu Za Zhi ; 41(7): 516-521, 2019 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-31357838

RESUMO

Objective: To investigate the effects and mechanisms of miR-144 on proliferation, apoptosis and cisplatin (DDP) resistance of neuroblastoma cells. Methods: Real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the mRNA expressions of miR-144 and MYCN in neuroblastoma cell lines, including SH-SY5Y and SK-N-SH, and human umbilical vein endothelial cells HUVEC. The miR-negative control, miR-144 mimics, si-negative control, si-MYCN, miR-144 mimics and pcDNA, miR-144 mimics and pcDNA-MYCN co-transfected SH-SY5Y cells were described as miR-NC, miR-144, si-NC, si-MYCN, miR-144+ pcDNA and miR-144+ pcDNA-MYCN group, respectively. The half maximal inhibitory concentration (IC(50)) and cell proliferation were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay. The protein expressions of MYCN, p21, cyclin D1, Bax, Bcl-2 were analyzed by western blot. Cell apoptosis was detected by flow cytometry. The cell fluorescence activity was detected by double luciferase reporter gene assay. Results: Compared with HUVEC cells, the expressions of miR-144 in neuroblastoma cells SH-SY5Y and SK-N-SH significantly decreased, while the mRNA and protein expression of MYCN significantly increased. The IC(50) of DDP was 9.16 µg/ml in SH-SY5Y cells. The absorbance value in 490nm (A(490) value) of miR-144 group was 0.30±0.03, significantly lower than 0.46±0.03 of miR-NC group. The cell apoptotic rate of miR-144 group was 26.94%±2.01%, significantly higher than 9.68%±0.52% of miR-NC group. The IC(50) value of DDP in miR-144 group was 2.95±0.26, significantly lower than 9.23±0.61 of miR-NC group. The expressions of p21, cyclin D1, Bax, Bcl-2 in miR-NC and miR-144 group were 2.67±0.19, 0.41±0.04, 2.12±0.21, 0.18±0.01 and 1.01±0.07, 1.00±0.06, 1.00±0.05, 1.00±0.06, respectively, with statistical significance (all P<0.05). Knockdown of MYCN showed the similar effects with those of miR-144 overexpression in SH-SYSY cells. MiR-144 significantly inhibited the fluorescence activity of ectopic MYCN expressing cells and negatively regulated the expression of MYCN. Overexpression of MYCN can reverse the effects of miR-144 on proliferation inhibition, apoptosis promotion and sensitization of SH-SY5Y cells to DDP. Conclusion: MiR-144 inhibits proliferation, promotes apoptosis and enhances the sensitivity of neuroblastoma cells to DDP through targeting MYCN, which provides a potential treatment for neuroblastoma.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Antineoplásicos/farmacologia , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Criança , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Oncology ; 97(3): 180-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31330520

RESUMO

BACKGROUND: Hormone receptor-positive breast cancer accounts for nearly two-thirds of breast cancer cases; it ultimately acquires resistance during endocrine treatment and becomes more aggressive. This study evaluated the role of developmental endothelial locus (Del)-1 in tamoxifen-resistant (TAM-R) breast cancer. METHODS: Del-1 expression in recurrent TAM-R breast cancer tissue was evaluated and compared to that in the original tumor tissue from the same patients. Del-1 expression was also evaluated in TAM-R cells by quantitative real-time PCR, western blotting, and enzyme-linked immunosorbent assay. The effects of Del-1 knockdown on the proliferation, migration, and invasion of TAM-R cells was assessed with wound-healing and Matrigel transwell assays. RESULTS: Del-1 was more highly expressed in recurrent breast cancer as compared to the original tumor tissues before initiation of endocrine treatment. Del-1 mRNA was upregulated in TAM-R and small interfering RNA-mediated knockdown of Del-1 suppressed the migration and proliferation of TAM-R cells while partly restoring TAM sensitivity. And the TAM resistance was recovered by knockdown of Del-1. CONCLUSIONS: TAM-R breast cancer is characterized by Del-1 overexpression and tumor progression can be inhibited by Del-1 depletion, which restores TAM sensitivity. Thus, therapeutic strategies that target Del-1 may be effective for the treatment of hormone-resistant breast cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Proteínas de Transporte/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Tamoxifeno/farmacologia , Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Técnicas de Silenciamento de Genes , Humanos , Interferência de RNA , RNA Interferente Pequeno
15.
Biochim Biophys Acta Rev Cancer ; 1872(1): 138-148, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348975

RESUMO

According to the most recent epidemiological studies, breast cancer shows the highest incidence and the second leading cause of death in women. Cancer progression and metastasis are the main events related to poor survival of breast cancer patients. This can be explained by the presence of highly resistant to chemo- and radiotherapy stem cells in many breast tumor tissues. In this context, numerous studies highlighted the possible involvement of epithelial to mesenchymal transition phenomenon as biological program to generate cancer stem cells, and thus participate to both metastatic and drug resistance process. Therefore, the comprehension of mechanisms (both cellular and molecular) involved in breast cancer occurrence and progression can lay the foundation for the development of new diagnostic and therapeutical protocols. In this review, we reported the most important findings in the field of breast cancer highlighting the most recent data concerning breast tumor biology, diagnosis and therapy.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Oncologia/tendências , Metástase Neoplásica
16.
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
17.
Nat Commun ; 10(1): 2399, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160585

RESUMO

Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSODK68Q is accompanied with a change of MnSOD's stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSODK68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression.


Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Resistencia a Medicamentos Antineoplásicos/genética , Superóxido Dismutase/genética , Acetilação , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Técnicas In Vitro , Lisina/metabolismo , Células MCF-7 , Camundongos , Mutação , Transplante de Neoplasias , Peroxidase/metabolismo , Estrutura Quaternária de Proteína/genética , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Tamoxifeno/uso terapêutico , Proteínas Supressoras de Tumor
18.
Nat Commun ; 10(1): 2385, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160589

RESUMO

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.


Assuntos
Antineoplásicos/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/metabolismo , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cristalização , Cristalografia por Raios X , Humanos , Mutação , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Ressonância de Plasmônio de Superfície
19.
Int J Oncol ; 55(1): 59-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180529

RESUMO

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase­3 mRNA regulation (miR­155­5p and miR­221­3p) in the temozolomide (TMZ)­resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug­resistance phenotype was obtained. Specificity of the PNA­mediated effects was analyzed by reverse transcription­quantitative polymerase­chain reaction, which demonstrated that the effects of R8­PNA­a155 and R8-PNA-a221 anti­miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide­resistant T98G glioma cell line. Notably, co­administration of both anti­miR­155 and anti­miR­221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co­treated with anti­miR­155 and anti­miR­221 PNAs.


Assuntos
Caspase 3/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , MicroRNAs/antagonistas & inibidores , Ácidos Nucleicos Peptídicos/farmacologia , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Glioma/enzimologia , Humanos , MicroRNAs/genética , Ácidos Nucleicos Peptídicos/genética
20.
Nat Commun ; 10(1): 2766, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235692

RESUMO

A major challenge in biology is that genetically identical cells in the same environment can display gene expression stochasticity (noise), which contributes to bet-hedging, drug tolerance, and cell-fate switching. The magnitude and timescales of stochastic fluctuations can depend on the gene regulatory network. Currently, it is unclear how gene expression noise of specific networks impacts the evolution of drug resistance in mammalian cells. Answering this question requires adjusting network noise independently from mean expression. Here, we develop positive and negative feedback-based synthetic gene circuits to decouple noise from the mean for Puromycin resistance gene expression in Chinese Hamster Ovary cells. In low Puromycin concentrations, the high-noise, positive-feedback network delays long-term adaptation, whereas it facilitates adaptation under high Puromycin concentration. Accordingly, the low-noise, negative-feedback circuit can maintain resistance by acquiring mutations while the positive-feedback circuit remains mutation-free and regains drug sensitivity. These findings may have profound implications for chemotherapeutic inefficiency and cancer relapse.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Modelos Genéticos , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Células CHO , Simulação por Computador , Cricetulus , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retroalimentação Fisiológica , Regulação da Expressão Gênica/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Puromicina/farmacologia , Puromicina/uso terapêutico , Processos Estocásticos
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