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1.
Braz. j. med. biol. res ; 54(9): e10390, 2021. graf
Article in English | LILACS | ID: biblio-1249337

ABSTRACT

Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.


Subject(s)
Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Drug Resistance, Neoplasm , MicroRNAs/genetics , Sorafenib/pharmacology , Liver Neoplasms/genetics , Liver Neoplasms/drug therapy , Signal Transduction , Gene Expression Regulation, Neoplastic , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Cell Proliferation , PTEN Phosphohydrolase/genetics , TOR Serine-Threonine Kinases
2.
Article in Chinese | WPRIM | ID: wpr-887903

ABSTRACT

Multi-drug resistance(MDR)refers to the loss of sensitivity of tumor cells to traditional chemotherapeutics agents under the mediation of various mechanisms,resulting in the reduction of chemotherapy efficacy.Current studies suggest that a variety of factors,including cell membrane transporter-mediated efflux of anti-tumor drugs,special microenvironment in tumor tissue,DNA self-repair and anti-apoptotic process,and epithelial-mesenchymal cell transformation,may contribute to the formation of MDR.Cell membrane transporter-mediated drug efflux refers to an increase in the amount of anti-tumor drug pumped out of the cell through the up-regulation of the ATP-binding cassette transporter on tumor cell membrane,which reduces the concentration of the drug in the cell,thus forming MDR.An effective method to inhibit the efflux pump caused by overexpression of membrane transporters plays an important role in overcoming MDR.As a promising drug delivery system,multifunctional nanoparticles have demonstrated many advantages in antitumor therapy.Meanwhile,nanoparticles with tailored design are capable of overcoming MDR when combined with a variety of strategies.This paper described in detail the studies relevant to the use of multifunctional nano-sized drug delivery system combined with different strategies,such as co-delivery of agents,external responsiveness or target modification for intervention with efflux pump in order to reverse MDR.This paper provides reference for the development of nano-sized drug delivery system and the formulation of reversal strategy in the future.


Subject(s)
Antineoplastic Agents/therapeutic use , Cell Membrane , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , Membrane Transport Proteins/therapeutic use , Multifunctional Nanoparticles , Nanoparticles , Neoplasms/drug therapy , Tumor Microenvironment
3.
Article in English | WPRIM | ID: wpr-887717

ABSTRACT

Objective@#To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells.@*Methods@#Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1).@*Results@#High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients.@*Conclusion@#The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis , Carcinoma, Ovarian Epithelial/metabolism , Cell Line, Tumor , Cofilin 1/metabolism , Drug Resistance, Neoplasm , Female , Humans , Ovarian Neoplasms/metabolism , Paclitaxel/therapeutic use , Phosphoprotein Phosphatases/metabolism , Phosphorylation
4.
Article in English | WPRIM | ID: wpr-922583

ABSTRACT

OBJECTIVES@#Lung cancer is one of the most common malignant tumors in the world, and its lethality ranks the first among many malignant tumors. For non-small cell lung cancer (NSCLC) patients, due to the high mortality rate, the overall 5-year survival rate is less than 15%. When NSCLC undergoes local invasion, the 5-year survival rate is only 20%, and it is even lower when distant metastasis occurs up to 4%. Almonertinib is an innovative drug independently researched and developed by China with independent intellectual property rights. As an epidermal growth factor receptor tyrosine kinase inhibitor, almonertinib is mainly used for locally advanced or metastatic NSCLC patients with epidermal growth factor receptor (EGFR) T790M mutation. This study aims to investigate the effects of almonertinib on the proliferation, invasion and migration of NSCLC cells in vitro.@*METHODS@#NSCLC cells H1975 and PC-9 were cultured in vitro. The effects of almonertinib on the proliferation, apoptosis, invasion, and migration of H1975 and PC-9 cells were detected by CCK-8 assay, apoptotic assay and Transwell assay. The expression of invasion and migration related proteins was detected by Western blotting.@*RESULTS@#The CCK-8 experiment showed that almonertinib inhibited the proliferation of H1975 and PC-9 cells in a time- and dose-dependent manner. The IC@*CONCLUSIONS@#Almonertinib can inhibit the proliferation, invasion, and migration of NSCLCH1975 and PC-9 cells in vitro and vivo, and promote the apoptosis of H1975 and PC-9 cells. The underlying mechanism may be related to the inhibition of tumor cell epithelial mesenchymal transformation and metalloproteinase expression.


Subject(s)
Acrylamides , Animals , Apoptosis , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Humans , Indoles , Lung Neoplasms , Mice , Mice, Nude , Mutation , Protein Kinase Inhibitors/pharmacology , Pyrimidines
5.
Journal of Experimental Hematology ; (6): 1714-1718, 2021.
Article in Chinese | WPRIM | ID: wpr-922323

ABSTRACT

OBJECTIVE@#To investigate the regulation of chronic myelogenous leukemia (CML) imatinib resistant genes, in order to improve the therapeutic effect of CML imatinib resistant patients.@*METHODS@#The human CML cell line K562 and imatinib-resistant K562 cells (K562/G01) were collected, and transcriptome of the cells were achieved by RNA-seq. The sequencing data were analyzed by using standard procedures.@*RESULTS@#Compared with K562 cells, 464 genes were significantly changed in K562/G01 cells, including 163 up-regulated and 301 down-regulated genes. The GO function annotation analysis and KEGG pathway analysis results showed that the differentially expressed genes were mainly involved in biological processes such as oxidative phosphorylation, localization to protein organelle, ribonucleoprotein complex biogenesis and so on. Gene Set Enrichment Analysis (GSEA) plots showed that 5 gene-sets were up-regulated in K562/G01 significantly, including the pathway of TGF-beta, mTOR and CML.@*CONCLUSION@#CML imatinib resistance is associated with oxidative phosphorylation, during which the pathway of TGF-beta and mTOR are significantly up-regulated.


Subject(s)
Drug Resistance, Neoplasm , Gene Expression Profiling , Humans , Imatinib Mesylate/pharmacology , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
6.
Journal of Experimental Hematology ; (6): 1704-1709, 2021.
Article in Chinese | WPRIM | ID: wpr-922321

ABSTRACT

OBJECTIVE@#To investigate the effect of ursane triterpenoids 3β,19α-dihydroxyursu-12-ene-23,28-dicarboxylic acid (Rotundioic acid, RA) on the sensitivity of adriamycin-resistant K562 cells (K562/ADM Cell) anti-tumor drug, and to explore the effect and mechanism of RA on the multidrug resistance of K562/ADM cells.@*METHODS@#CCK-8 method was used to detect the effect of RA on the sensitivity of K562 cells and K562/ADM cells to anti-tumor drug. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the expression level of mRNA and the protein in K562 and K562/ADM cells, and the effect of RA on the expression of MDR1 mRNA and P-gp in K562/ADM cells was also detected; Western blot was used to detect the expression of p-JNK, p-p38 and p-ERK1/2 in K562/ADM cells.@*RESULTS@#RA could increased the sensitivity of K562/ADM cells to adriamycin(the reversal factor was 1.61 times), the difference showed statistically significantly (P<0.05); the resistance factor of K562/ADM to ADM was 41.76 times. The expression of MDR1 mRNA in K562 cells was extremely low, and the protein product P-glycoprotein (P-gp) was almost not expressed; MDR1 mRNA and P-gp in K562/ADM cells were highly expressed; RA could down-regulate the expression levels of MDR1 and P-gp in K562/ADM cells. In addition, RA could upregulate the phosphorylation levels of p38 and ERK1/2 in K562/ADM cells, but it has no effect on the expression of p-JNK.@*CONCLUSION@#RA may participate in the regulation of MAPK signaling pathway by upregulating the expression levels of p-p38 and p-ERK1/2 in K562/ADM cells, and thus inhibit the transcription and translation levels of MDR1, and finally reverse the multidrug resistance of leukemia cells.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , K562 Cells
7.
Journal of Experimental Hematology ; (6): 1403-1410, 2021.
Article in Chinese | WPRIM | ID: wpr-922272

ABSTRACT

OBJECTIVE@#To establish cytarabine-resistant acute lymphoblastic leukemia (ALL) cell lines and investigate its possible resistant mechanism.@*METHODS@#Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The cell viability was detected by CCK-8 assay, and the distribution of cell cycle was detected by flow cytometry. Real-time fluorescence quantitative PCR was used to detect the mRNA expression levels of multidrug resistant gene and Ara-C metabolic enzymes. The expression levels of cyclin were detected by Western blot.@*RESULTS@#Jurkat/Ara-C and Nalm-6/Ara-C drug-resistant cell lines were successfully established, the resistance index of which was 1 973.908±161.163 and 7 231.643± 1 190.624, respectively. Drug-resistant cell lines had no cross-resistance to commonly used chemotherapeutic drugs, such as doxorubicin. Flow cytometry showed that the ratio of G@*CONCLUSION@#Cytarabine-resistant ALL cell lines are successfully established by using low concentration continuous induction method, and its drug-resistant mechanism may be related to the deficiencies of DCK and cyclinB1.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Cell Line , Cytarabine/pharmacology , Drug Resistance, Neoplasm , Humans , Neoplasm Proteins , Precursor Cell Lymphoblastic Leukemia-Lymphoma
8.
Article in Chinese | WPRIM | ID: wpr-921529

ABSTRACT

Objective To establish a human colon cancer cell line HCT-116/5-FU resistant to 5-fluorouracil(5-FU)and explore the relationship between runt-related transcription factor 3(RUNX3)and drug resistance of colorectal cancer.Methods The human colon cancer cell line HCT-116/5-FU with resistance to 5-FU was established by low concentration gradient increment combined with high-dose intermittent shock.CCK-8 method was used to determine the half maximal inhibitory concentration(IC


Subject(s)
Cell Line, Tumor , Colonic Neoplasms/genetics , Core Binding Factor Alpha 3 Subunit , Drug Resistance, Neoplasm , Fluorouracil/pharmacology , Humans , Transcription Factor 3
9.
Article in Chinese | WPRIM | ID: wpr-880087

ABSTRACT

OBJECTIVE@#To investigate the effect of etoposide (ETO) on elimination of chronic myeloid leukemia (CML) stem cells by imatinib mesylate(IM) in vivo.@*METHODS@#SCL-tTA/BCR-ABL mice were used as CML animal model. Flow cytometry was used to assess the effect of ETO alone or in combination with IM on the number of leukemia stem cell (LSC) in bone marrow and spleen, and peripheral blood neutrophils in CML mice and normal control FVB mice.@*RESULTS@#The results showed that in CML mice, the number and proportion of LSC in bone marrow and the proportion of neutrophils in peripheral blood decreased significantly after ETO and IM combined treatment, and the degree of decrease was more significant than that of both alone. While in wild type FVB mice, the combination of ETO and IM showed no significant effect on the number and proportion of LSK cells in bone marrow and the proportion of neutrophils in spleen.@*CONCLUSION@#ETO can selectively enhance elimination of CML LSC by IM in vivo.


Subject(s)
Animals , Drug Resistance, Neoplasm , Etoposide , Fusion Proteins, bcr-abl , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mice , Stem Cells
10.
Article in English | WPRIM | ID: wpr-879944

ABSTRACT

The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate,fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly,the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly,tumor stromal cells including adipocyte,fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly,the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance,in terms of transporters,tumor microenvironment and metabolic enzymes,to provide insight for improving the therapeutic efficacy for drug-resistant tumors.


Subject(s)
Cell Line, Tumor , Drug Resistance, Neoplasm , Glutamine/metabolism , Glycolysis , Humans , Neoplasms/drug therapy , Oxidative Phosphorylation , Tumor Microenvironment
11.
Article in Chinese | WPRIM | ID: wpr-880829

ABSTRACT

OBJECTIVE@#To establish a mouse model bearing orthotopic temozolomide (TMZ)-resistant glioma that mimics the development of drug resistance in gliomas @*METHODS@#Seventy-eight adult C57BL/6 mice were randomly divided into 6 groups (@*RESULTS@#The mouse models bearing TMZresistant glioma was successfully established. The cells from the high-dose induced group showed a significantly higher colony-forming rate than those from the high-dose control group (@*CONCLUSIONS@#Progressive increase of TMZ doses in mice bearing orthotopic gliomas can effectively induce TMZ resistance of the gliomas.


Subject(s)
Animals , Antineoplastic Agents, Alkylating/pharmacology , Brain Neoplasms/drug therapy , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm , Glioma/drug therapy , Mice , Mice, Inbred C57BL , Temozolomide/therapeutic use
12.
Article in English | WPRIM | ID: wpr-880693

ABSTRACT

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can effectively inhibit the growth of EGFR-dependent mutant non-small cell lung cancer (NSCLC). Unfortunately, NSCLC patients often develop severe drug resistance after long-term EGFR-TKI treatment. Studies have shown that the disorder of energy metabolism in tumor cells can induce EGFR-TKI resistance. Due to the drug action, gene mutation and other factors, tumor cells undergo metabolic reprogramming, which increases the metabolic rate and intensity of tumor cells, promotes the intake and synthesis of nutrients (such as sugar, fat and glutamine), forms a microenvironment conducive to tumor growth, enhances the bypass activation, phenotype transformation and abnormal proliferation of tumor cells, and inhibits the activity of immune cells and apoptosis of tumor cells, ultimately leading to drug resistance of tumor cells to EGFR-TKI. Therefore, targeting energy metabolism of NSCLC may be a potential way to alleviate TKI resistance.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Epidermal Growth Factor , ErbB Receptors/genetics , Humans , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Tumor Microenvironment
13.
Int. braz. j. urol ; 46(3): 353-362, May-June 2020. tab, graf
Article in English | LILACS | ID: biblio-1090612

ABSTRACT

ABSTRACT Purpose: Testicular germ cells tumor (TGCT) are associated with a high cure rate and are treated with platinum-based chemotherapy. However, a group of testicular cancer patients may have a very unfavorable evolution and insensitivity to the main therapeutic agent chemotherapy (CT) cisplatin. The aim of this study was to evaluate the risk of recurrence and overall survival related to the expression of nuclear factor kappa-B (NF-κB), transglutaminase 2 (TG2) and excision repair cross-complementation group 1 (ERCC1) in patients with TGCT treated with platinum combinations. Patients and Methods: A retrospective study was performed with TGCT patients treated with platinum-based chemotherapy. Immunohistochemical analysis was performed and the expression was correlated with clinical and laboratory data. Results: Fifty patients were included, the mean age was 28.4 years (18 to 45), and 76% were non-seminoma. All patients were treated with standard cisplatin, etoposide and bleomycin or cisplatin, and etoposide. Patient's analyzed immunodetection for NF-κB, TG2, and ERCC1 were positive in 76%, 54% and 42%, respectively. Multivariate analysis identified that positive expressions to ERCC1 and NF-κB are independent risk factors for higher recurrence TGCT after chemotherapy (RR 2.96 and 3.16, respectively). Patients with positive expression of ERCC1 presented a poor overall survival rate for 10-year follow (p=0.001). Conclusions: The expression of ERCC1 and NF-κB give a worse prognosis for relapse, and only ERCC1 had an influence on the overall survival of TGCT patients treated with platinum-based chemotherapy. These may represent markers that predict poor clinical outcome and response to cisplatin.


Subject(s)
Humans , Male , Adult , Testicular Neoplasms , Transglutaminases/metabolism , NF-kappa B/metabolism , GTP-Binding Proteins/metabolism , Lung Neoplasms , Prognosis , Antineoplastic Combined Chemotherapy Protocols , Retrospective Studies , Cisplatin , Drug Resistance, Neoplasm/physiology , DNA-Binding Proteins , DNA Repair , Endonucleases
14.
Braz. j. med. biol. res ; 53(5): e9330, 2020. tab, graf
Article in English | LILACS | ID: biblio-1098112

ABSTRACT

The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.


Subject(s)
Humans , Stomach Neoplasms/metabolism , Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , MicroRNAs/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Glycolysis/genetics , Transfection , Gene Expression Regulation, Neoplastic , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Real-Time Polymerase Chain Reaction , Flow Cytometry , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics
15.
Biol. Res ; 53: 18, 2020. tab, graf
Article in English | LILACS | ID: biblio-1124204

ABSTRACT

BACKGROUND: Cisplatin resistance (DDP-resistance) remains one of the major causes of poor prognosis in females with ovarian cancer. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of cellular processes, including chemoresistance. The aim of this study was to explore the role of HOX transcript antisense RNA (HOTAIR) in DDP-resistant ovarian cancer cells. METHODS: DDP-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. Real-time PCR, western blot, dual-luciferase reporter assay, and flow cytometry were then used to evaluate the effect of HOTAIR/miR-138-5p axis on chemoresistance of DDP-resistant ovarian cancer cells to DDP. RESULTS: We found that HOTAIR was upregulated in DDP-resistant cells, while miR-138-5p was downregulated. Knockdown of HOTAIR increased the expression of miR-138-5p in DDP-resistant cells and miR-138-5p is directly bound to HOTAIR. Upregulation of miR-138-5p induced by HOTAIR siRNA or by its mimics enhanced the chemosensitivity of DDP-resistant cells and decreased the expression of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1). Furthermore, the HOTAIR silencing-induced chemosensitivity of DDP-resistant cells was weakened by miR-138-5p inhibitor. CONCLUSIONS: These data demonstrate that HOTAIR acts as a sponge of miR-138-5p to prevent its binding to EZH2 and SIRT1, thereby promoting DDP-resistance of ovarian cancer cells. Our work will shed light on the development of therapeutic strategies for ovarian cancer treatment.


Subject(s)
Humans , Female , Ovarian Neoplasms/genetics , Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , RNA, Long Noncoding/genetics , Gene Expression Regulation, Neoplastic/drug effects , Up-Regulation , Apoptosis/drug effects , MicroRNAs/antagonists & inhibitors , Cell Line, Tumor , Gene Knockout Techniques/methods , Sirtuin 1/antagonists & inhibitors , Real-Time Polymerase Chain Reaction , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors
16.
Journal of Experimental Hematology ; (6): 2093-2096, 2020.
Article in Chinese | WPRIM | ID: wpr-880021

ABSTRACT

Tyrosine kinase inhibitor (TKI) has significantly improved the treatment of chronic myeloid leukemia (CML), however the resistance often resulted in treatment failure. Currently, it is known that the survival of CML cells can be affected by regulating autophagy, oxidative stress and mitochondrial metabolism, among which autophagy is an evolution-conserved catabolism process, and closely related to the pathogenesis of CML, thus playing a dual role in regulating the biological characteristics of cells. On the one hand, autophagy can promote the apoptosis of CML cells, and also can induce the drug resistance of CML cells on the other hand. In this review, the effect of autophagy on CML cells was summarzed briefly, so as to provide a useful idea to explore the combination of TKI with the autophagy inhibitor or inducer to overcome the resistance of CML to TKI.


Subject(s)
Apoptosis , Autophagy , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors/pharmacology , Research
17.
Journal of Experimental Hematology ; (6): 1064-1068, 2020.
Article in Chinese | WPRIM | ID: wpr-827160

ABSTRACT

Abstract  Chronic myeloid leukemia (CML) is a malignant myeloproliferative tumor which is originating from hematopoietic stem cells. Chemotherapy is the preferred made of treatment for the disease. However, in recent years, more and more patients have multidrug resistance (MDR) during treatment, which is the main cause of failure treatment, therefore, the search for effective reversal agents has important clinical significance. Traditional Chinese medicine derived reversal agents have the characteristics of multiple targets, low toxicity and high efficiency, which can reverse the drug resistance through different mechanisms, and the research potential is unlimited. In recent years, it has been widely concerned by scholars at home and abroad, especially the research on physcion, emodin, curcumin, matrine, gambogic acid, oridonin, ligustrazine, solanine and other monomers, which has made great advance. In this reviwe, the recent research advance on the reversal of MDR in chronic myeloid leukemia by Chinese medicine monomer is summarized briefly.


Subject(s)
Antineoplastic Agents , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drugs, Chinese Herbal , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Medicine, Chinese Traditional
18.
Article in Chinese | WPRIM | ID: wpr-878785

ABSTRACT

To prepare peptide-modified chitosan tetramethylprazine nanoparticles(FGF-CS-TMP-NPS) and investigate its reversal effect on multidrug resistance in tumor cells. The pEGF-CS-TMP-NPs were prepared by ion crosslinking method, and their physicochemical properties were investigated. Western blot was used to detect the expression levels of epidermal growth factor receptor(EGFR)(MCF-7, MCF-7/ADR, K562 and K562/ADR) and drug-resistant related protein P-gp. MCF-7/ADR and K562/ADR were selected as cell models. The cytotoxicity of pEGF-CS-TMP-NPs, the multiple of cell resistance to adriamycin, the reversal resistance index of pEGF-CS-TMP-NPs to doxorubicin and the sensitization of pEGF-CS-TMP-NPs to doxorubicin were detected by MTT assay. After MCF-7/ADR and K562/ADR were treated with pEGF-CS-TMP-NPs, the expression changes of P-gp were detected by Western blot. The encapsulation efficiency and drug loading of pEGF-CS-TMP-NPs were 37.66%± 0.53% and 3.25%± 0.34% respectively in HPLC. The nanoparticles showed an average particle size of(150.50±9.3) nm, polymer dispersity index of(0.059±0.007) and Zeta potential of(19.30±2.02) mV as detected by laser particle size analyzer. The nanoparticles were spherical and well dispersed under transmission electron microscope. Western blot results showed that EGFR was positively expressed in MCF-7 and MCF-7/ADR cells, while negatively expressed in K562 and K562/ADR cells. P-gp was highly expressed in MCF-7/ADR and K562/ADR, while negatively expressed in MCF-7 and K562. pEGF-CS-TMP-NPs had a weak effect on MCF-7/ADR and K562/ADR. The adriamycin resistance of MCF-7/ADR cells was 108.36 times, and that of K562/ADR cells was more than 100 times. When IC_(85) of pEGF-CS-TMP-NPs was used as the administration concentration, the reversion index of MCF-7/ADR and K562/ADR cells was 3.68 and 1.87, respectively. pEGF-CS-TMP-NPs could enhance the sensitivity of adriamycin to MCF-7/ADR cells in a positive correlation with the concentration, and the sensitivity was significantly higher than that of K562/ADR cells. Western blot results showed that the expression level of P-gp in MCF-7/ADR cells decreased significantly after treatment with pEGF-CS-TMP-NPs, while the expression level of P-gp in K562/ADR cells did not change significantly. Experimental results show that pEGF-CS-TMP-NPs have an active targeting effect on MCF-7/ADR cells with high EGFR expression, and can effectively reverse the multidrug resistance of MCF-7/ADR cells. Active targeting effect is related to the peptides modification of nanoparticles, and the mechanism of reversing tumor MDR may be achieved by down-regulating the expression level of P-gp.


Subject(s)
Breast Neoplasms , Chitosan , Doxorubicin , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , Nanoparticles , Peptides , Pyrazines
19.
Article in Chinese | WPRIM | ID: wpr-829046

ABSTRACT

OBJECTIVE@#To investigate the effect of Bmi-1 gene silencing on drug resistance of leukemia cell K562/ADR and to explore its possible mechanism.@*METHODS@#After two sequences of Bmi-1-siRNA were transfected into drug-resistant K562/ADR cells, the mRNA and protein expressions of Bmi-1 gene were detected. After Bmi-1 gene silencing the expression of P-gp and MDR1 were detected and the accumulation of doxorubicin in K562/ADR cells were detected by flow cytometry to determine the effect of Bmi-1 gene silencing on drug resistance of K562/ADR cells. The protein expression of NF-κB was analyzed after Bmi-1 gene silencing. Then after K562/ADR cells were treated with NF-κB inhibitor PDTC, the protein expression of P-gp and its functional changes were analyzed to determine the effect of NF-κB on drug resistance of leukemia cells. The protein expressions of PTEN, AKT and p-AKT after Bmi-1 gene silencing were detected and the effect of Bmi-1 gene silencing on PTEN/PI3K/AKT signaling pathway in drug-resistant cells was determined. After K562/ADR cells were treated with PI3K/AKT pathway inhibitor LY294002, the protein expressions of NF-κB and P-gp were analyzed to determine the regulation of AKT on the expression of NF-κB and P-gp. The protein expressions of AKT, p-AKT, NF-κB and P-gp were detected after the Bmi-1-siRNA transfected cells were treated by PTEN inhibitor BPV. Above-mentioned expression of mRNA was detected by RT-PCR, and the protein expression was detected by Western blot.@*RESULTS@#The expression of Bmi-1 gene in K562/ADR cells decreased at both mRNA and protein levels and the doxorubicin accumulation increased after Bmi-1 gene silencing. The expression of MDR1/P-gp in Bmi-1-siRNA transfected cells was lower than that in K562/ADR cells (P<0.05). After Bmi-1 gene silencing, the activity of NF-κB decreased. The activity of NF-κB and P-gp expression was inhibited and the function of P-gp in K562/ADR cells was reduced by using NF-κB inhibitor (PDTC). The protein expression of PTEN increased while the protein expression of p-AKT decreased after Bmi-1 gene silencing (P<0.05). The protein expressions of p-AKT, P-gp and the activity of NF-κB were inhibited significantly by using PI3K/AKT inhibitor LY294002 (P<0.05). After the Bmi-1-siRNA transfected cells were treated by PTEN inhibitor BPV, the activity of NF-κB and the protein expressions of P-gp were restored.@*CONCLUSION@#Bmi-1 plays a key role in MDR-mediated multidrug resistance in K562/ADR cells, which may be mediated by activating PTEN/AKT pathway to regulate NF-κB.


Subject(s)
Doxorubicin , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , K562 Cells , Mitogen-Activated Protein Kinase 7
20.
Article in Chinese | WPRIM | ID: wpr-828918

ABSTRACT

OBJECTIVE@#To investigate the effect of down-regulation of pannexin 2 (Panx-2) channels on cisplatin-induced apoptosis in I-10 cells.@*METHODS@#The expression of Panx-2 protein in testicular cancer cells was detected with Western blotting. The testicular cancer cell line I-10 was transfected with two short hairpin RNA (shRNA1 and shRNA2) Lipofectamine, the empty vector (NC group) or Lipofectamine2000 (blank control group), and the changes in the expression of Panx-2 was detected with Western blotting. The effects of transfection with a Panx-2 inhibitor on surviving fraction of the cells treated with cisplatin (16 μmol/L) for 24 h, 48 h and 72 h was assessed with MTT assay, and the clonogenic capacity of the cells was evaluated with colony-forming assay. At 8 h after incubation with 16 μmol/L cisplatin, AnnexinV/PI double staining was used to detect the early apoptosis of the cells. After 24 h of treatment with 16 μmol/L cisplatin, the cells were examined for expressions of caspase-3, Bcl-2 and Bax using Western blotting.@*RESULTS@#The expression of Panx-2 was significantly increased in cisplatin-resistant I-10/DDP ( < 0.001) cells and Tcam-2/DDP ( < 0.01) cells as compared with I-10 cells and Tcam-2 cells. Transfection of I-10 cells with shRNA1 and shRNA2 resulted in significantly decreased Panx-2 expression ( < 0.05) and significantly reduced cell surviving fraction ( < 0.001). In the presence of cisplatin, the cells in NC group showed a higher clonogenic efficiency than those in shRNA1 and shRNA2 groups ( < 0.001). The early-stage apoptosis rate of the cells in shRNA1 and shRNA2 groups were significantly higher than that in NC group ( < 0.01). Panx-2 knockdown in I-10 cells significantly increased caspase-3 and Bax expressions ( < 0.05) and significantly decreased the expression of Bcl-2 ( < 0.01).@*CONCLUSIONS@#Down-regulation of Panx-2 channel enhances cisplatin-induced apoptosis in cultured testicular cancer cells.


Subject(s)
Antineoplastic Agents , Apoptosis , Cell Line, Tumor , Cell Proliferation , Cisplatin , Connexins , Down-Regulation , Drug Resistance, Neoplasm , Humans , Male , Testicular Neoplasms
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