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1.
Tumour Biol ; 42(9): 1010428320957506, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32914709

RESUMO

The development of the multidrug resistance phenotype is one of the major challenges faced in the treatment of cancer. The multidrug resistance phenotype is characterized by cross-resistance to drugs with different chemical structures and mechanisms of action. In this work, we hypothesized that the acquisition of resistance in cancer is accompanied by activation of the epithelial-to-mesenchymal transition process, where the tumor cell acquires a more mobile and invasive phenotype; a fundamental step in tumor progression and in promoting the invasion of other organs and tissues. In addition, it is known that atypical glycosylations are characteristic of tumor cells, being used as biomarkers. We believe that the acquisition of the multidrug resistance phenotype and the activation of epithelial-to-mesenchymal transition provoke alterations in the cell glycophenotype, which can be used as glycomarkers for chemoresistance and epithelial-to-mesenchymal transition processes. Herein, we induced the multidrug resistance phenotype in the PC-3 human prostate adenocarcinoma line through the continuous treatment with the drug paclitaxel. Our results showed that the induced cell multidrug resistance phenotype (1) acquired a mixed profile between epithelial and mesenchymal phenotypes and (2) modified the glycophenotype, showing an increase in the level of sialylation and in the number of branched glycans. Both mechanisms are described as indicators of poor prognosis.


Assuntos
Adenocarcinoma/patologia , Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Paclitaxel/farmacologia , Adenocarcinoma/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Glicosilação , Humanos , Células PC-3 , Fenótipo
2.
Nat Commun ; 11(1): 4640, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934232

RESUMO

Small molecule inhibitors are prime reagents for studies in microtubule cytoskeleton research, being applicable across a range of biological models and not requiring genetic engineering. However, traditional chemical inhibitors cannot be experimentally applied with spatiotemporal precision suiting the length and time scales inherent to microtubule-dependent cellular processes. We have synthesised photoswitchable paclitaxel-based microtubule stabilisers, whose binding is induced by photoisomerisation to their metastable state. Photoisomerising these reagents in living cells allows optical control over microtubule network integrity and dynamics, cell division and survival, with biological response on the timescale of seconds and spatial precision to the level of individual cells within a population. In primary neurons, they enable regulation of microtubule dynamics resolved to subcellular regions within individual neurites. These azobenzene-based microtubule stabilisers thus enable non-invasive, spatiotemporally precise modulation of the microtubule cytoskeleton in living cells, and promise new possibilities for studying intracellular transport, cell motility, and neuronal physiology.


Assuntos
Microtúbulos/química , Paclitaxel/química , Linhagem Celular Tumoral , Citoesqueleto/química , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Humanos , Isomerismo , Microtúbulos/metabolismo , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Paclitaxel/farmacologia
3.
Int J Nanomedicine ; 15: 6409-6420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922008

RESUMO

Aim: Tumor cell-derived microparticles (MP) can function as a targeted delivery carrier for anti-tumor drugs. Here, we aimed to generate paclitaxel-loaded microparticles (MP-PTX) from HeLa cells and examined its therapeutic potential on human cervical carcinoma. Methods: MP-PTX was generated from HeLa cells by ultraviolet radiation and subsequent centrifugation. The particle size, drug loading rate, and stability of MP-PTX were examined in vitro. Flow cytometry and the MTT assay were performed to test the inhibitory effect of MP-PTX using different cell lines. Immunodeficient mice bearing HeLa cervical carcinoma were treated with 0.9% normal saline, MP, paclitaxel (PTX) (2.5 mg/kg), or MP-PTX (PTX content identical to PTX group) every day for 6 consecutive days. Tumor volume and animal survival were observed. Micro 18F-FDG PET/CT was performed to monitor the therapeutic efficacy. The proliferation activity of cells and microvessel density in tumor tissues were determined by immunohistochemical staining using Ki-67 and CD31, respectively. Results: Dynamic laser scattering measurements showed that the particle size of MP-PTX was 285.58 ± 2.95 nm and the polydispersity index was 0.104 ± 0.106. And the particle size of MP-PTX was not change at 4°C for at least one week. More than 1% of PTX in the medium could be successfully encapsulated into HeLa cell-derived MP. When compared with PTX, MP-PTX treatment significantly increased apoptosis of tumor cells and reduced their proliferation. In addition, MP-PTX showed lower toxicity to normal human umbilical vein endothelial cells (HUVEC) than PTX. In vivo studies further demonstrated that MP-PTX treatment significantly inhibited the growth of cervical carcinoma, prolonged the survival of tumor-bearing mice, and reduced the toxicity of PTX. Immunohistochemical staining revealed that MP-PTX treatment led to decreased Ki-67 positive tumor cells and decreased microvessel density in tumor tissues. Conclusion: Our results demonstrated that HeLa-derived MP-PTX significantly enhanced the anti-cancer effects of PTX with reduced toxicity, which may provide a novel strategy for the treatment of cervical carcinoma.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Paclitaxel/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Portadores de Fármacos/química , Células Endoteliais/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Paclitaxel/farmacologia , Tamanho da Partícula
4.
Int J Nanomedicine ; 15: 4899-4918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764924

RESUMO

Purpose: The use of chemotherapeutic agents to combat cancer is accompanied by high toxicity due to their inability to discriminate between cancer and normal cells. Therefore, cancer therapy research has focused on the targeted delivery of drugs to cancer cells. Here, we report an in vitro study of folate-poly(ethylene glycol)-poly(propylene succinate) nanoparticles (FA-PPSu-PEG-NPs) as a vehicle for targeted delivery of the anticancer drug paclitaxel in breast and cervical cancer cell lines. Methods: Paclitaxel-loaded-FA-PPSu-PEG-NPs characterization was performed by in vitro drug release studies and cytotoxicity assays. The NPs cellular uptake and internalization mechanism were monitored by live-cell imaging in different cancer cell lines. Expression of folate receptor-α (FOLR1) was examined in these cell lines, and specific FOLR1-mediated entry of the FA-PPSu-PEG-NPs was investigated by free folic acid competition. Using inhibitors for other endocytic pathways, alternative, non-FOLR1 dependent routes for NPs uptake were also examined. Results: Drug release experiments of Paclitaxel-loaded PPSu-PEG-NPs indicated a prolonged release of Paclitaxel over several days. Cytotoxicity of Paclitaxel-loaded PPSu-PEG-NPs was similar to free drug, as monitored in cancer cell lines. Live imaging of cells treated with either free Paclitaxel or Paclitaxel-loaded PPSu-PEG-NPs demonstrated tubulin-specific cell cycle arrest, with similar kinetics. Folate-conjugated NPs (FA-PPSu-PEG-NPs) targeted the FOLR1 receptor, as shown by free folic acid competition of the FA-PPSu-PEG-NPs cellular uptake in some of the cell lines tested. However, due to the differential expression of FOLR1 in the cancer cell lines, as well as the intrinsic differences between the different endocytic pathways utilized by different cell types, other mechanisms of nanoparticle cellular entry were also used, revealing that dynamin-dependent endocytosis and macropinocytosis pathways mediate, at least partially, cellular entry of the FA-PPSu-PEG NPs. Conclusion: Our data provide evidence that Paclitaxel-loaded-FA-PPSu-PEG-NPs can be used for targeted delivery of the drug, FA-PPSu-PEG-NPs can be used as vehicles for other anticancer drugs and their cellular uptake is mediated through a combination of FOLR1 receptor-specific endocytosis, and macropinocytosis. The exploration of the different cellular uptake mechanisms could improve treatment efficacy or allow a decrease in dosage of anticancer drugs.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Ácido Fólico/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Receptor 1 de Folato/metabolismo , Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Paclitaxel/química , Paclitaxel/farmacologia
5.
Anticancer Res ; 40(6): 3129-3138, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487607

RESUMO

BACKGROUND/AIM: The combination of paclitaxel and carboplatin is the standard chemotherapy for ovarian cancer. Previous studies have implied that vitamin D (1,25-D3) may have growth inhibitory effects in ovarian cancer. This study aimed to investigate the effect of paclitaxel, carboplatin and 1,25-D3 on the growth of ovarian cancer cells in vitro, based on the hypothesis that 1,25-D3 might potentiate the effect of paclitaxel and/or carboplatin. MATERIALS AND METHODS: Three non-commercial ovarian carcinoma cell lines UT-OV-1(mucinous), UT-OV-3B (serous) and UT-OV-4 (endometrioid) were exposed to different concentrations of 1,25-D3, paclitaxel and carboplatin, respectively. The cell viability was measured using a Crystal violet assay kit. The cellular vitamin D receptor (VDR) mRNA levels were measured by qRT-PCR using the LightCycler equipment. RESULTS: The growth-inhibitory effect of the combination of paclitaxel and carboplatin was 56% in UT-OV-1, 33% in UT-OV-3B and 47% in UT-OV-4 cells. Single 1,25-D3 (10 µM) inhibited the growth of UT-OV-3B and UT-OV-4 by 23% and 28%, respectively, whereas no effect was seen in UT-OV-1 cells. These results are in line with the finding that the expression of VDR was high in UT-OV-3B and UT-OV-4, but very low in UT-OV-1. The combination of 1,25-D3, paclitaxel and carboplatin resulted in 61%, 46% and 58% growth reduction in UT-OV-1, UT-OV-3B and UT-OV-4 cells, respectively. The additive effect of 1,25-D3 was 21% in UT-OV-4, 20% in UT-OV-3B and 12% in UT-OV-1 cell line. CONCLUSION: The results imply that combining 1,25-D3 with paclitaxel and carboplatin may potentiate their growth inhibitory effect on ovarian cancer cells with high VDR expression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Técnicas In Vitro/métodos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Receptores de Calcitriol/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia
6.
Int J Nanomedicine ; 15: 3433-3445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32523342

RESUMO

Background: Reconstituted lipoproteins (rLips) based on endogenous lipid nanostructures has been increasingly regarded as an excellent and promising antitumor drug delivery. However, some problems relating to the main component, apolipoprotein, for instance, rare source, unaffordable price, and low specificity of relevant receptor expression, become chief obstacles to its broad development and application. Purpose: The primary aim of this study is to develop biomimetic rLips by utilizing folic acid (FA)-modified bovine serum albumin (BSA) as a replacement for apolipoprotein and demonstrate its tumor targeting and antitumor efficacy. Methods: The amino groups of BSA were covalently conjugated with FA through the amide reaction. PTX-loaded nanostructured lipid carrier (termed as P-NLC) consisting of phospholipid, cholesteryl ester, triglyceride and cholesterol was prepared by the emulsification-evaporation method and utilized as the lipid core. FA-modified BSA (FA-BSA) was characterized for the protein substitute degree and attached with NLC by incubation-insert method to form the lipoprotein-mimic nanocomplex (termed as PFB-rLips). The morphology of nanoparticles was observed under transmission electron microscopy (TEM), and the particle size and zeta potential were determined using dynamic light scattering. In vitro release behavior of PTX from PFB-rLips was investigated with the dialysis method. Hemolysis tests were conducted to evaluate the biosecurity of PFB-rLips. Cell uptake and cytotoxicity assays were performed on human hepatocytes (LO2) and human hepatoma cells (HepG2). Tumor targeting was assessed using in vivo imaging system in H22 tumor-bearing mice model. Antitumor efficacy in vivo was investigated and compared between Taxol® (paclitaxel) formulation and PTX-incorporated nanoparticles in the same tumor model. Results: A fixed molar ratio 50:1 of FA to BSA was chosen as the optimal input ratio based on the balance between appropriate degree of protein substitution and amphiphilicity of FA-BSA. The morphology of FB-rLips exhibited as a homogeneous spherical structure featured by lipid cores surrounded with a cloudy protein shell observed under TEM. The particle size, zeta potential and encapsulation efficiency were 174.6±3.2 nm, -17.26±0.9 mV and 82.2±2.4%, respectively. In vitro release behavior of PTX from PFB-rLips was slow and sustained. The uptake of FB-rLips was much higher in HepG2 cells than in LO2 cells. Furthermore, the uptake of FB-rLips was significantly higher than that of rLips without FA involved (termed as B-rLips) and NLC in HepG2 cells. Hemolysis and cytotoxicity assays showed good biocompatibility of FB-rLips. The internalization mechanism of FB-rLips mainly depended on clathrin-mediated and caveolin-mediated endocytosis coupling with energy consumption, and FA receptors expressed on tumor cells played a critical role in cellular uptake process. CCK-8 studies demonstrated that PFB-rLips exhibited significantly better tumor killing ability than Taxol® (paclitaxel) formulation in vitro. Moreover, FB-rLips produced more excellent tumor-targeting properties than NLC through in vivo imaging assays. On the basis of this, PTX-loaded FB-rLips also performed more remarkable anticancer activity than other therapy groups in H22 tumor-bearing mice. Conclusion: FB-rLips would serve as a potential nanocarrier for improving tumor-targeting and therapeutic efficacy while reducing the side effects on normal tissues and organs.


Assuntos
Portadores de Fármacos/química , Ácido Fólico/uso terapêutico , Lipoproteínas/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Ácido Fólico/síntese química , Ácido Fólico/química , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Tamanho da Partícula , Coelhos , Soroalbumina Bovina/química , Eletricidade Estática
7.
Int J Nanomedicine ; 15: 3319-3331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494132

RESUMO

Background: It is of great significance to develop intelligent co-delivery systems for cancer chemotherapy with improved therapeutic efficacy and few side-effects. Materials and Methods: Here, we reported a co-delivery system based on pH-sensitive polyprodrug micelles for simultaneous delivery of doxorubicin (DOX) and paclitaxel (PTX) as a combination chemotherapy with pH-triggered drug release profiles. The physicochemical properties, drug release profiles and mechanism, and cytotoxicity of PTX/DOX-PMs have been thoroughly investigated. Results and Discussion: The pH-sensitive polyprodrug was used as nanocarrier, and PTX was encapsulated into the micelles with high drug-loading content (25.6%). The critical micelle concentration (CMC) was about 3.16 mg/L, indicating the system could form the micelles at low concentration. The particle size of PTX/DOX-PMs was 110.5 nm, and increased to approximately 140 nm after incubation for 5 days which showed that the PTX/DOX-PMs had high serum stability. With decrease in pH value, the particle size first increased, and thenwas no longer detectable. Similar change trend was observed for CMC values. The zetapotential increased sharply with decrease in pH. These results demonstrated the pHsensitivity of PTX/DOX-PMs. In vitro drug release experiments and study on release mechanism showed that the drug release rate and accumulative release for PTX and DOX were dependent on the pH, showing the pH-triggered drug release profiles. Cytotoxicity assay displayed that the block copolymer showed negligible cytotoxicity, while the PTX/DOX-PMs possessed high cytotoxic effect against several tumor cell lines compared with free drugs and control. Conclusion: All the results demonstrated that the co-delivery system based on pH-sensitive polyprodrug could be a potent nanomedicine for combination cancer chemotherapy. In addition, construction based on polyprodrug and chemical drug could be a useful method to prepare multifunctional nanomedicine.


Assuntos
Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Micelas , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Células NIH 3T3 , Neoplasias/patologia , Paclitaxel/farmacologia , Tamanho da Partícula , Polímeros/química , Eletricidade Estática
8.
Life Sci ; 256: 117943, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32531377

RESUMO

AIM: The aim of this study was to improve the therapeutic index of chemotherapeutic drugs on glioblastoma cells through an improved co-drug delivery system. MATERIALS AND METHODS: Methotrexate (MTX) and paclitaxel (PTX) were co-loaded into poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) coated with polyvinyl alcohol (PVA) and Poloxamer188 (P188). KEY FINDINGS: The mean size of the NPs was about 212 nm, with a zeta potential of about -15.7 mV. Encapsulation efficiency (EE%) and drug loading (DL%) were determined to be 72% and 4% for MTX and 85% and 4.9% for PTX, respectively. The prepared NPs were characterized by differential thermal analysis (DTA) and thermogravimetric analysis (TGA). Moreover, an in vitro sustained release profile was observed for both drug loaded PLGA NPs. Glioblastoma cellular uptake of the NPs was confirmed by fluorescence microscopy and cell survival rate was investigated through the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method after 48 h of incubation showing IC50 values of 24.5 µg·mL-1 for PTX and 9.5 µg·mL-1 for MTX for the MTX/PTX co-loaded PLGA nanoparticles coated with PVA/P188 (Co-2 NPs). Apoptosis and necrosis were also studied via flow cytometry, the lactate dehydrogenase (LDH) assay and the amount of anti-apoptotic protein (Bcl-2) expression. Blood compatibility of the co-delivery of PTX and MTX loaded PLGA NPs was investigated using a hemolysis method as well. SIGNIFICANCE: The co-delivery of PTX and MTX loaded PLGA NPs is promising for the treatment of glioblastoma compared to their respective free drug formulations and, thus, should be further investigated.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Composição de Medicamentos , Glioblastoma/tratamento farmacológico , Metotrexato/uso terapêutico , Nanopartículas/química , Paclitaxel/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacologia , Apolipoproteínas/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Glioblastoma/patologia , Hemólise/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , L-Lactato Desidrogenase/metabolismo , Metotrexato/farmacologia , Nanopartículas/ultraestrutura , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos
9.
Anticancer Res ; 40(5): 2475-2479, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366391

RESUMO

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. RESULTS: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). CONCLUSION: Eribulin has clinical potential for triple-negative MPBC patients.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Feminino , Furanos/uso terapêutico , Humanos , Cetonas/uso terapêutico , Camundongos , Paclitaxel/farmacologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 20-26, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376564

RESUMO

OBJECTIVE: To investigate the effect of overexpression of leukemia inhibitory factor (LIF) on cisplatin and paclitaxel resistance of endometrial cancer cells in vitro. METHODS: Endometrial cancer cell lines HEC-1B and RL95-2 were infected with a recombinant lentivirus to overexpress LIF, and the changes in LIF expression was verified using RT-qPCR and ELISA. The viability of the LIF-overexpressing cells was assessed using CCK-8 assay, and the cell apoptosis and changes in mitochondrial membrane potential in response to cisplatin or paclitaxel treatment were analyzed with annexin V-FITC/PI staining and JC-1 assay, respectively. The effect of LIF overexpression on the expressions of Bcl-2 family proteins and STAT3 pathway was evaluated using Western blotting; dual-luciferase reporter gene assay was employed to detect the transcriptional activity of STAT3. The effect of STAT3 silencing on apoptosis of the LIF-overexpressing cells induced by cisplatin or paclitaxel was investigated. RESULTS: The cell lines infected with the recombinant lentivirus showed significantly increased mRNA and protein levels of LIF (P < 0.05) without obvious changes in the cell viability (P>0.05). LIF overexpression significantly attenuated cisplatin-or paclitaxel-induced apoptosis of the endometrial cancer cells (P < 0.05) and markedly increased mitochondrial membrane potential of the cells (P < 0.05). The expressions of Bcl-2, Bcl-xL and p-STAT3 proteins increased obviously while the expressions of Bax, Bad and STAT3 either decreased or showed no obvious changes in the LIF-overexpressing cells. Overexpressing LIF significantly enhanced the transcriptional activity of STAT3 (P < 0.05), and silencing STAT3 obviously enhanced apoptosis of the endometrial cancer cells overexpressing LIF (P < 0.05). CONCLUSIONS: s Overexpression of LIF can enhance cisplatin and paclitaxel resistance to endometrial cancer cells in vitro.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Endométrio/genética , Fator Inibidor de Leucemia/genética , Paclitaxel/farmacologia , Transdução de Sinais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína bcl-X/metabolismo
11.
Anticancer Res ; 40(5): 2955-2960, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366448

RESUMO

BACKGROUND/AIM: Currently, there is no recommendation for the treatment of breast cancer (BC) with bone-marrow cell infiltration (BMI). We evaluated the efficacy and safety of weekly-paclitaxel in this population. PATIENTS AND METHODS: This retrospective study included all BC patients with BMI receiving weekly-paclitaxel between January 2014 and May 2018. Overall-survival (OS) was the primary endpoint. Secondary endpoints were progression-free-survival (PFS) and safety. RESULTS: BMI was diagnosed in 26 patients. This infiltration was suggested by peripheral blood smear in 73% of cases. All patients had anemia, and 77% had thrombocytopenia. OS and PFS were 7.2 months [95% confidence interval (CI)=2.6-20.7] and 3.3 months (95%CI=1.6-7.2), respectively. Good performance-status, absence of thrombocytopenia and presence of less than 5% of circulating erythroblasts at BMI diagnosis, were associated with better survival. One patient presented grade 5 febrile neutropenia but no episodes of bleeding were reported. CONCLUSION: Weekly-paclitaxel is an effective therapeutic option with limited toxicity for BC with BMI.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/farmacologia , Análise de Sobrevida
12.
Hum Cell ; 33(3): 850-858, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32452013

RESUMO

The chemoresistance of tumors is the main barrier to cancer treatment. Interleukin-22 (IL-22) plays an important role in the chemoresistance of multi-cancers; however, the roles of IL-22 in the paclitaxel resistance of lung adenocarcinoma cells remain to be investigated. The present study aims to investigate the potential mechanisms of IL-22 enhancing the chemoresistance of lung adenocarcinoma cells to paclitaxel. We cultured A549, H358, and A549/PTX cell lines. qRT-PCR and western blot assays were performed to examine the mRNA and/or protein levels of IL-22 in A549, A549/PTX, H358, and H358/PTX. Moreover, cells were transfected with IL-22 siRNA1, IL-22 siRNA2, and siRNA NC, and treated with paclitaxel, and the proliferation rate of lung adenocarcinoma cells was evaluated by MTT assay. Flow cytometry was conducted to determine the apoptosis rate of lung adenocarcinoma cells. The results showed that the expression of IL-22 in lung adenocarcinoma tissues was higher than that in normal tissues, and the expression of IL-22 was higher in A549/PTX and H358/PTX compared with A549 and H358 cells. Meanwhile, the expression of IL-22 was strongly correlated with smoking history and TMN stage, as well. Furthermore, IL-22 siRNA inhibited the proliferation and promoted the apoptosis of A549/PTX and H358/PTX cells, and IL-22 siRNA also suppressed the expression levels of AKT and Bcl-2 and increased the expression levels of Bax and cleaved caspase 3. To sum up, IL-22 may mediate the chemosensitivity of lung adenocarcinoma cells to paclitaxel through inhibiting the AKT signaling pathways.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Interleucinas/genética , Interleucinas/fisiologia , Neoplasias Pulmonares/patologia , Paclitaxel/farmacologia , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Expressão Gênica , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Transdução de Sinais , Fumar/efeitos adversos
13.
AAPS PharmSciTech ; 21(5): 151, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32440910

RESUMO

Triple-negative breast (TNBC) cancer that is upregulated with epidermal growth factor receptor (EGFR), and devoid of both the hormonal receptors and epidermal growth factor receptor 2 (HER 2), has led to a concept of treating TNBC with EGFR-targeted therapeutics. The combination of paclitaxel (PTX) and piperine (PIP) may improve the bioavailability of paclitaxel for cancer therapy. TPGS (vit E-PEG 1000-succinate)-coated liposomes were prepared with PTX alone or in combination with PIP, and either with (targeted) or without (non-targeted) cetuximab (CTX) conjugation. The Bradford assay indicated that 75% of CTX has been conjugated on the liposomes. The size and percent encapsulation of PTX&PIP co-loaded liposomes were found to be in the range of 204 to 218 nm and 31-73%, respectively. The drug release rate was found to be higher at pH 5.5 in comparison with release at pH 6.4 and pH 7.4. Cellular uptake and toxicity studies on MDA-MB-231 cells showed that PTX&PIP co-loaded targeted liposomes have demonstrated superior uptake and cytotoxicity than their non-targeted counterparts. The IC50 values of both of the liposomal formulations were found to be significantly higher than PTX control. Indeed, combining PIP with PTX control has improved the cytotoxicity of PTX control, which proved the synergistic anticancer effect of PIP. Lyophilized liposomes showed an excellent stability profile with the size range between 189 and 210 nm. Plasma stability study revealed a slight increase in the particle size due to the adsorption of plasma proteins on the surface of liposomes. The long-term stability study also indicated that liposomes were stable at 4°C.


Assuntos
Alcaloides/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Benzodioxóis/uso terapêutico , Paclitaxel/uso terapêutico , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Benzodioxóis/farmacologia , Linhagem Celular Tumoral , Composição de Medicamentos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Receptores ErbB/efeitos dos fármacos , Feminino , Liofilização , Humanos , Lipossomos , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Receptor ErbB-2
14.
Nat Commun ; 11(1): 2350, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393766

RESUMO

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Azepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Modelos Biológicos , Mutação/genética , Paclitaxel/farmacologia , Piperazinas/farmacologia , Ploidias , Proteínas/metabolismo , Piridinas/farmacologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Resultado do Tratamento , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
15.
Environ Toxicol ; 35(9): 1015-1028, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32420678

RESUMO

Breast cancer (BC) is the leading cause of cancer-related death in women worldwide and one of the most prevalent malignancy. In recent years, increasing evidence had illuminated that long noncoding RNAs (lncRNAs) serve as critical factors in multiple tumor progression, including BC. Emerging references had indicated that the lncRNA H19 acts as significant roles in tumor progression and epithelial-mesenchymal transition (EMT). However, the underlying molecular mechanisms and biological roles of H19 in BC invasion, metastasis and EMT are still unclear. In this study, it was detected that the expression level of H19 was increased in BC paclitaxel-resistant (PR) cells subline (MCF-7/PR) in comparison with MCF-7 parental cells. In vitro, there were demonstrated that H19 overexpression promoted BC cells proliferation, metastasis, invasion and EMT procedures, and suppressed cells apoptosis. Whereas, H19 suppression resulted in the contrary biological effects. Besides, bioinformatics tools and dual-luciferase reporters assays indicated that miR-340-3p could act as a potential target gene of H19, the underlying mechanism studies proved that H19 could act as a competing endogenous RNA (ceRNA) via competitively binding miR-340-3p to promote BC cell proliferation, metastasis and EMT by regulating tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) and potentiate the Wnt/ß-catenin signaling in BC cells. In summary, our findings demonstrated that H19 could act as a ceRNA in BC progression, metastasis and EMT through modulating miR-340-3p/YWHAZ axis and activating the canonical Wnt/ß-catenin signaling pathway, indicating that H19 might act as an underlying therapeutic target and prognostic biomarker for BC therapy.


Assuntos
Proteínas 14-3-3/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MicroRNAs/genética , Paclitaxel/farmacologia , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
16.
Tumour Biol ; 42(4): 1010428320914477, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32342732

RESUMO

Triple-negative breast cancers are the most aggressive subtypes with poor prognosis due to lack of targeted cancer therapy. Recently, we reported an association of A-kinase anchor protein 4 expression with various clinico-pathological parameters of breast cancer patients. In this context, we examined the effect of knockdown of A-kinase anchor protein 4 on cell cycle, apoptosis, cellular proliferation, colony formation, migration, and invasion in triple-negative breast cancer cells. We also examined the synergistic cytotoxic effect of paclitaxel on A-kinase anchor protein 4 downregulated triple-negative breast cancer cells. Knockdown of A-kinase anchor protein 4 resulted in significant reduction in cellular growth and migratory abilities. Interestingly, we also observed enhanced cell death in A-kinase anchor protein 4 downregulated cells treated with paclitaxel. Knockdown of A-kinase anchor protein 4 in cell cycle resulted in G0/G1 phase arrest. Knockdown of A-kinase anchor protein 4 also led to increased reactive oxygen species generation as a result of upregulation of NOXA and CHOP. In addition, levels of cyclins, cyclin-dependent kinases, anti-apoptotic molecules, and mesenchymal markers were reduced in A-kinase anchor protein 4 downregulated cells. Moreover, downregulation of A-kinase anchor protein 4 also caused tumor growth reduction in in vivo studies. These data together suggest that A-kinase anchor protein 4 downregulation inhibits various malignant properties and enhances the cytotoxic effect of paclitaxel, and this combinatorial approach could be useful for triple-negative breast cancer treatment.


Assuntos
Proteínas de Ancoragem à Quinase A/deficiência , Neoplasias de Mama Triplo Negativas/genética , Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Imunofenotipagem , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Paclitaxel/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Nanomedicine ; 15: 2337-2349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308385

RESUMO

Purpose: The aim of this study was to develop an "all-in-one" nanoplatform that integrates at the second near-infrared (NIR-II) region dye IR1061 and anticancer drug paclitaxel (PTX) into an apoferritin (AFN) nanocage (IR-AFN@PTX). Simultaneously, folic acid (FA), tumor target molecule,  was conjugated onto IR-AFN@PTX to be IR-AFN@PTX-FA for tumor-targeted and pH/NIR-II-triggered synergistic photothermal-chemotherapy. Methods: IR1061 was firstly reacted with PEG and then conjugated with AFN to be IR-AFN. Then, FA was conjugated onto the surface of IR-AFN to be IR-AFN-FA. At last, PTX was incorporated into IR-AFN-FA to fabricate a nanoplatform IR-AFN@PTX-FA. The NIR-II photothermal properties and pH/NIR-II triggered drug release were evaluated. The ability of IR-AFN@PTX-FA to target tumors was estimated using optical bioluminescence. In vitro and in vivo synergistic therapeutic effects of pH/NIR-II-triggered and tumor-targeted photothermal-chemotherapy were investigated in 4T1 tumor model. Results: IR-AFN@PTX-FA showed excellent water solubility and physiological stability, which significantly enhanced the solubility of both IR1061 and PTX. After 5 min of laser irradiation at 1064 nm, IR-AFN@PTX-FA exhibited an effective photothermal effect compared with laser irradiation at 808 nm, even when blocked with 0.6 cm thick chicken breast. Cellular uptake experiments showed IR-AFN@PTX-FA utilized clathrin-mediated and caveolae-mediated endocytosis pathways to enter 4T1 cells, and was then delivered by the endosome to the lysosome. NIR-II laser irradiation and pH could synergistically trigger PTX release, inducing significant tumor inhibition in vitro and in vivo. Conclusion: As a novel "all-in-one" nanoplatform, IR-AFN@PTX-FA was found to selectively target tumors and showed very efficient NIR-II photothermal effects and pH/NIR-II triggered drug release effects, showing a remarkable, synergistic photothermal-chemotherapy effect.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Boratos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Piranos/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Apoferritinas/química , Linhagem Celular Tumoral , Corantes/química , Liberação Controlada de Fármacos , Ácido Fólico/química , Ácido Fólico/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Lasers , Camundongos Endogâmicos BALB C , Nanopartículas/química , Paclitaxel/farmacocinética , Fototerapia/métodos , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Pharmacol Exp Ther ; 373(3): 453-462, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32238452

RESUMO

Paclitaxel (PTX) is an antineoplastic drug extracted from the Taxus species, and peripheral neuropathy is a common side effect. Paclitaxel-induced peripheral neuropathy (PIPN) seriously affects patient quality of life. Currently, the mechanism of PIPN is still unknown, and few treatments are recognized clinically. Duloxetine is recommended as the only potential treatment of chemotherapy-induced peripheral neuropathy (CIPN) by the American Society of Clinical Oncology. However, this guidance lacks a theoretical basis and experimental evidence. Our study suggested that duloxetine could improve PIPN and provide neuroprotection. We explored the potential mechanisms of duloxetine on PIPN. As a result, duloxetine acts by inhibiting poly ADP-ribose polymerase cleavage (PARP) and tumor suppressor gene p53 activation and regulating apoptosis regulator the Bcl2 family to reverse PTX-induced oxidative stress and apoptosis. Taken together, the present study shows that using duloxetine to attenuate PTX-induced peripheral nerve injury and peripheral pain may provide new clinical therapeutic targets for CIPN. SIGNIFICANCE STATEMENT: This study reported that duloxetine significantly alleviates neuropathic pain induced by paclitaxel and is related to poly ADP-ribose polymerase (PARP), tumor suppressor gene p53, and apoptosis regulator the Bcl2 family. Our findings thus not only provide important guidance to support duloxetine to become the first standard chemotherapy-induced peripheral neuropathy (CIPN) drug but also will find potential new targets and positive control for new CIPN drug development.


Assuntos
Cloridrato de Duloxetina/farmacologia , Paclitaxel/farmacologia , Traumatismos dos Nervos Periféricos/induzido quimicamente , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Chem Biol Interact ; 323: 109074, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32217108

RESUMO

Non-small-cell lung cancer (NSCLC) is one of the common malignant tumors, and multidrug resistance (MDR) and tumor metastasis limit the anticancer effect of NSCLC. Therefore, it is necessary to develop new anticancer drug that can inhibit MDR and metastasis of NSCLC. In the present study, we found that 5-(2-chlorophenyl)-4-(4-(3,5-dimethoxyphenyl)piperazine-1-carbonyl)-2H-1,2,3- triazole (MAY) displayed strong cytotoxic effect on A549 and taxol-resistant A549 cells (A549/Taxol cells). We further discovered that MAY led to G2/M phase arrest by inhibiting microtubule polymerization in both cells. Then MAY caused apoptosis by the mitochondrial pathway in A549 cells and through the extrinsic pathway in A549/Taxol cells. Interestingly, MAY was not a substrate for P-glycoprotein (P-gp), which was highly expressed in A549/Taxol cells, and MAY inhibited the expression and efflux function of P-gp. Furthermore, MAY inhibited epithelial-mesenchymal transition (EMT) by targeting Twist1 in A549/Taxol cells. In summary, our results suggest that MAY induces apoptosis in A549 and A549/Taxol cells and inhibits EMT in A549/Taxol cells. These findings suggest that MAY could provide a promising method for the treatment of NSCLC, especially for the treatment of resistant NSCLC.


Assuntos
Apoptose/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Paclitaxel/farmacologia , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Nucleares/metabolismo , Paclitaxel/química , Polimerização , Transdução de Sinais/efeitos dos fármacos , Triazóis/química , Moduladores de Tubulina/química , Proteína 1 Relacionada a Twist/metabolismo
20.
Med Sci Monit ; 26: e918216, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32129321

RESUMO

BACKGROUND Chemoresistance is a primary hindrance for current cancer treatments. The influence of abnormal mitochondria in chemotherapy resistance is not well known. To explore the correlation between mitochondria and acquired chemoresistance, this work studied alterations in mitochondrial dynamics, biogenesis, and functions for paclitaxel-resistant cancer cell line A549/Taxol and its parental line A549. MATERIAL AND METHODS Mitochondrial morphology was observed by transmission electron microscopy and confocal microscopy. We measured the mitochondrial mass and mitochondrial membrane potential using fluorescent dyes. The glucose metabolic profile and ATP (adenosine triphosphate) content were determined by bioluminescent cell assays. Seahorse bio-energy analyzer XF24 was used to detect the mitochondrial respiratory function. The expressions of mitochondrial dynamics and biogenesis related genes were quantified using real-time polymerase chain reaction. RESULTS We observed fusion morphology of the mitochondrial network in A549/Taxol cells, with upregulation of fusion genes (Mfn1 and Mfn2) and downregulation of fission gene Fis1. In A549/Taxol cells, mitochondrial mass showed a significant decrease, while the mitochondrial biogenesis pathway was strongly activated. Despite the decreased mitochondrial membrane potential, the capability for mitochondrial respiration was not impaired in A549/Taxol cells. CONCLUSIONS Our study revealed a series changes of mitochondrial characteristics in paclitaxel-resistant cells. Mfn1 and Mfn2 and PGC-1alpha increased, while Fis1 expression and mitochondrial oxidative phosphorylation decreased in A549/Taxol cell lines. These changes to mitochondrial fusion, fission, and biological function contributed to the occurrence of paclitaxel resistance in tumor cells which induced paclitaxel resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Dinâmica Mitocondrial , Biogênese de Organelas , Paclitaxel/farmacologia , Células A549 , GTP Fosfo-Hidrolases/metabolismo , Humanos , Potencial da Membrana Mitocondrial , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Mitocôndrias/ultraestrutura , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Mitocondriais/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
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