Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed that downregulation of a transcription-associated gene (ZNRD1) could reverse the resistant phenotype of gastric cancer cells through regulation of the transcription of multidrug resistance gene 1 (MDR1). In the present study, we determined both known and novel differentially expressed genes in VCR-induced multidrug resistant gastric cancer cell SGC7901/VCR transfected with ZNRD1 siRNA or empty vector control. Screening was performed using the Human Cancer Xpro(tm) HC-III plus arrays, containing 3072 cancer-related cDNAs. Ten genes, involved in cell cycle control, nucleic acid binding, and protein phosphorylation, among other functions, underwent more than 5-fold change. Of the downregulated genes we chose Inosine monophosphate dehydrogenase 2 (IMPDH2) for further validation by quantitative RT-PCR. In vitro and in vivo drug sensitivity analyses revealed that inhibition of ZNRD1 and IMPDH2 activity sensitized SGC7901/VCR cells to methotrexate. Additionally, inhibition of ZNRD1 could suppress adriamycin-induced apoptosis and significantly downregulate the expression of Bcl-2, but it did not alter the expression of the glutathione-S-transferase, or intracellular glutathione content. Taken together, the findings suggest that ZNRD1 could act as a modulator of methotrexate chemotherapy in gastric cancer cells through the regulation of IMPDH2 and Bcl-2.
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PMID:ZNRD1 mediates resistance of gastric cancer cells to methotrexate by regulation of IMPDH2 and Bcl-2. 1660 1

Mitotic arrest deficient 2 (MAD2) is an essential component of the mitotic spindle checkpoint pathway. It was previously shown to be associated with drug resistance of tumor cells. To further explore the roles of MAD2 in responses of gastric cancer cells to chemotherapy drugs, we constructed the siRNA vectors of MAD2 and transfected them into gastric cancer SGC7901 cells to inhibit expression of MAD2. MTT assay showed that the downregulation of MAD2 increased the resistance of SGC7901 cells to spindle inhibitors and DNA damaging agents. The apoptosis rates of gastric cancer cells transfected with MAD2-siRNA were 10.7% and 10%, respectively, after treated by 1.0microg/ml VCR and cisplatin. In contrast, the apoptosis rates of SGC7901 and SGC7901/psilencer3.1 induced by VCR were 43.2%, 38.7%; and that induced by cispaltin were 34.1%, 31.4%. The ratio of Bcl-2 to Bax was much higher in the MAD2-siRNA transfectants compared with the SGC7901/psilencer. In SGC7901/psilencer, cytochrome c and cleaved caspase 3 protein levels increased along with the exposure time increased. However, these protein levels of SGC7901/MAD2-siRNA had no changes during the drug treatment. These results indicate that down regulation of MAD2 could promote the drug resistance of gastric cancer cells and inhibit anticancer drugs induced-apoptosis by upregulating Bcl-2 and interfering the mitochondrion apoptosis pathway.
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PMID:Depression of MAD2 inhibits apoptosis of gastric cancer cells by upregulating Bcl-2 and interfering mitochondrion pathway. 1671

The transmembrane transport pump P-glycoprotein (P-gp) causes the efflux of chemotherapeutic agents from cells and is an important system that secures multidrug resistance (MDR) of neoplastic cells. In the present study drug sensitive L1210 and multidrug resistant L1210/VCR mouse leukemic cell lines were used as an experimental model. We found that LY 294,002, a specific inhibitor of PI3K/Akt kinase pathway, reduced the degree of vincristine resistance in L1210/VCR cells significantly and in a concentration-dependent manner. This was accompanied by decrease in IC(50) value to vincristine from 3.195+/-0.447 to 1.898+/-0.676 micromol/l for 2 micromol/l, to 0.947+/-0.419 micromol/l for 4 micromol/l, and to 0.478+/-0.202 micromol/l for 8 micromol/l LY294,002. The IC(50) value of sensitive cells for vincristine was about 0.010 micromol/l. FACS analysis of the proportion of cells in apoptosis or necrosis by annexin-V apoptosis kit showed the following: (i) vincristine-induced apoptosis in resistant cell to a much lower extent than in sensitive cells; (ii) LY294,002 alone did not induce apoptosis or necrosis in both sensitive and resistant cells; (iii) LY294,002 applied together with vincristine significantly increased the number of apoptotic cells. Transport activity of P-gp in resistant cells was monitored using calcein/AM as substrate and was depressed by LY294,002 in a concentration dependent manner. Significant differences in calcein retention were not observed when cells were preincubated with LY294,002 at different times from 0.5 to 24h. Sensitive and resistant cells contain similar amounts of uncleaved (i.e., unactivated) caspase-3 but in latter cells the activation of caspase-3 by proteolytic cleavage was decreased. The reversal of vincristine resistance by LY294,002 was associated with marked activation of caspase-3. Western blot analysis revealed that the development of MDR phenotype in L1210/VCR cells was also associated with increased level of Bcl-2 protein. All the above findings point to the possible involvement of PI3K/Akt kinase pathway in modulation of P-gp mediated multidrug resistance in L1210/VCR mouse leukemic cell line. MDR reversal effect of LY294,002 is accompanied with this compound's influence on vincristine-induced apoptosis.
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PMID:LY294,002, a specific inhibitor of PI3K/Akt kinase pathway, antagonizes P-glycoprotein-mediated multidrug resistance. 1701 May 77

We investigated the role of cytokine-induced apoptosis inhibitor 1 (CIAPIN1), a newly identified apoptosis inhibitor, in leukemia cell multidrug resistance (MDR) and its possible underlying mechanisms. CIAPIN1 was found to be overexpressed at the mRNA and protein levels in the vincristine-induced multidrug-resistant leukemia cell line HL-60/VCR, compared with HL-60, its parental cell line. In this study, we transfected HL-60 with a eukaryotic expression vector of CIAPIN1. In vitro drug sensitivity assays suggested that HL-60-CIAPIN1 cells conferred resistance to both P-glycoprotein (P-gp)-related and -unrelated drugs. Blocking CIAPIN1 expression in HL-60/VCR cells by CIAPIN1-specific small interfering RNA increased the cells' sensitivity to various chemotherapeutic drugs. Flow cytometry results suggested that CIAPIN1 expression could suppress adriamycin-induced apoptosis, accompanied by a decreased accumulation and increased release of adriamycin. Semiquantitative RT-PCR, Western blot analysis, and luciferase reporter assays suggested that CIAPIN1 could significantly upregulate the expression of MDR-1 and Bcl-2, the transcription of the MDR-1 gene, as well as downregulate the expression of Bax. Additionally, the inhibition of CIAPIN1 expression by RNA interference or P-gp inhibitor could partially reverse CIAPIN1-mediated MDR. Taken together, our findings suggest that downregulating CIAPIN1 could sensitize leukemia cells to chemotherapeutic drugs by downregulating MDR-1 and Bcl-2 and by upregulating Bax, yet not altering either glutathione-S-transferase activity or intracellular glutathione content in leukemia cells. Further study of CIAPIN1's function may reveal more of the mechanisms of leukemia MDR and result in the development of strategies to treat leukemia.
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PMID:A new apoptosis inhibitor, CIAPIN1 (cytokine-induced apoptosis inhibitor 1), mediates multidrug resistance in leukemia cells by regulating MDR-1, Bcl-2, and Bax. 1805 32

This study investigated the effects of human bone marrow fibroblastoid stromal cell line (HFCL) on the proliferation, differentiation and chemosensitivity of acute myeloid leukemia cells (AML) in vitro coculture. By setting up coculture system of sensitive U937, HL-60 cell line and multidrug-resistant (MDR) HL-60/VCR cells in direct contact with human bone marrow fibroblastoid stromal cell line HFCL, or separated by transwell, the proliferation of AML cells cocultured with HFCL cells was inhibited, compared with AML cells alone. And NBT positive cells increased slightly. The percentage of G1 phase cells of AML cells cocultured with HFCL cells was higher than that without HFCL cells, and that of S phase cells was lower. The expression of CD11b and CD14 increased. Meanwhile HL-60 and HL-60/VCR cells treated by TPT were observed to have apoptosis characteristic morphological changes. The proportion of G0/G1 HL-60 and HL-60/VCR cells treated with TPT increased and the sub-G1 increased. The percentage of Annexin V-positive cells and apoptotic cells increased with expression of activated Caspase-3 and the reduced expression of Bcl-2. But when they were cocultured with HFCL cells, the percentage of Annexin V-positive cells and apoptotic cells decreased and sub-G1 reduced. After indirect contact with HFCL cells the expression of activated Caspase-3 decreased and the expression of Bcl-2 increased. After direct contact with HFCL cells for 96 h, the expression levels of 582 genes in HL-60 cells were up-regulated, and 1,323 genes were down-regulated at least twofold by Affymetrix GeneChip Human Genome U133 set A. The expression change in some genes, such as HL14, was confirmed by RT-PCR and northern blot. In a word, HFCL cells could inhibit the proliferation, induce the monocytic differentiation of U937, HL-60 and HL-60/VCR cells, and prevent TPT-induced apoptosis in HL-60 and HL-60/VCR cells via modulation of Bcl-2 and active Caspase-3. Many genes might take part in the influence of HFCL cells on AML cells, which may give important insights into the interaction of bone marrow stromal cells and leukemic cells.
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PMID:Effects of human bone marrow stromal cell line (HFCL) on the proliferation, differentiation and apoptosis of acute myeloid leukemia cell lines U937, HL-60 and HL-60/VCR. 1828 67

Multidrug resistance (MDR) is a major impediment to the effective chemotherapy of many human malignancies. Although much effort has been devoted to develop new drugs for overcoming MDR, until now, still no useful method of reversing MDR, suitable for clinical use, has emerged from this large quantity of work. Some researchers have reported that proteasome inhibitors could induce apoptosis in a variety of cancer cells. In the present study, we found that, in vincristine-resistant human gastric cancer cell line SGC7901/VCR, proteasome inhibitor MG132 was an effective inducer of apoptosis, and also had the capacity of downregulating the expression of anti-apoptotic Bcl-2 and MDR1 (P-gp), by which MG132 resensitized tumor cells to the apoptosis induced by anticancer drugs. Data presented by drug sensitivity assay further demonstrated that MG132 could reverse the resistant phenotype of gastric cancer cells effectively through both enhancing drug-induced apoptosis and inhibiting P-gp. The further study of the effectiveness and safety of proteasome inhibitor in vivo may be helpful for developing a new possible strategy to treat gastric cancer MDR.
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PMID:Proteasome inhibitor MG132 reverses multidrug resistance of gastric cancer through enhancing apoptosis and inhibiting P-gp. 1829 17

microRNAs are endogenous small noncoding RNAs that regulate gene expression negatively at posttranscriptional level. This latest addition to the complex gene regulatory circuitry revolutionizes our way to understanding physiological and pathological processes in the human body. Here we investigated the possible role of microRNAs in the development of multidrug resistance (MDR) in gastric cancer cells. microRNA expression profiling revealed a limited set of microRNAs with altered expression in multidrug- resistant gastric cancer cell line SGC7901/VCR compared to its parental SGC7901 cell line. Among the downregulated microRNAs are miR-15b and miR-16, members of miR-15/16 family, whose expression was further validated by qRT-PCR. In vitro drug sensitivity assay demonstrated that overexpression of miR-15b or miR-16 sensitized SGC7901/VCR cells to anticancer drugs whereas inhibition of them using antisense oligonucleotides conferred SGC7901 cells MDR. The downregulation of miR-15b and miR-16 in SGC7901/VCR cells was concurrent with the upregulation of Bcl-2 protein. Enforced mir-15b or miR-16 expression reduced Bcl-2 protein level and the luciferase activity of a BCL2 3' untranslated region-based reporter construct in SGC7901/VCR cells, suggesting that BCL2 is a direct target of miR-15b and miR-16. Moreover, overexpression of miR-15b or miR-16 could sensitize SGC7901/VCR cells to VCR-induced apoptosis. Taken together, our findings suggest that miR-15b and miR-16 could play a role in the development of MDR in gastric cancer cells at least in part by modulation of apoptosis via targeting BCL2.
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PMID:miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. 1844 91

Although chemotherapy plays an important role in combined treatment of human gliomas, it fails to bring about satisfactory outcomes in a number of patients. One of the major obstacles in this treatment is the development of multidrug resistance (MDR) during treatment. Regulation of MDR in the context of gliomas is poorly understood, and clinical efforts to inhibit it have not been fruitful. Activation of the Hedgehog (HH) pathway has been shown to contribute to the growth, maintenance and relapse of various cancers. As data were not available on the role of Gli1 expression in glioma progression, we analyzed the correlation between Gli1 expression and tumor recurrence after chemotherapy in 60 glioma samples. The effects of inhibiting or activating the HH pathway on sensitizing or rendering glioma cell lines resistant to VCR, VP16, CDDP and ACNU, which are widely used in clinical chemotherapy, were determined. Additionally, the impact of the HH pathway on the expressions of MDR1, MRP1, MVP, MGMT, Bcl-2 and Survivin genes was determined. Our results indicate that overexpression of Gli1 is correlated with glioma recurrence after chemotherapy. We further show that the HH pathway activity can promote clonogenic survival of glioma cell lines in chemotherapy. Additionally, we found that blocking the HH pathway enhanced cytotoxicity of chemotherapeutic agents in glioma cells, through down-regulating the expressions of MDR1, MRP1, MVP, MGMT, Bcl-2 and Survivin genes. Taken together, these results suggest that Gli1 plays a dominant role in chemoresistance of glioma cells, and that suppression of Gli1 expression might be a valid therapeutic option for overcoming MDR and for increasing the success of chemotherapy.
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PMID:Gli1 is a potential target for alleviating multidrug resistance of gliomas. 1981 66

Here we firstly investigated the role of miR-138 in multidrug resistance of leukemia cells. miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin. miR-138 could significantly down-regulate the expression of P-glycoprotein, Bcl-2, and the transcription of the multidrug resistance gene 1. Further study of the biological functions of miR-138 might be helpful for developing possible strategies to treat leukemia.
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PMID:miR-138 might reverse multidrug resistance of leukemia cells. 2828 24

Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy. We evaluated the effect of daunorubicin (DNR)-loaded magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) on K562-n/VCR cells in vivo. K562-n and its MDR counterpart K562-n/VCR cell were inoculated into nude mice subcutaneously. The mice were randomly divided into four groups: group A received normal saline, group B received DNR, group C received MNPs-Fe3O4, and group D received DNR-loaded MNPs-Fe3O4. For K562-n/VCR tumor, the weight was markedly lower in group D than that in groups A, B, and C. The transcriptions of Mdr-1 and Bcl-2 gene were significantly lower in group D than those in groups A, B, and C. The expression of Bcl-2 was lower in group D than those in groups A, B, and C, but there was no difference in the expression of P-glycoprotein. The transcriptions and expressions of Bax and caspase-3 in group D were increased significantly when compared with groups A, B, and C. In conclusion, DNR-loaded MNPs-Fe3O4 can overcome MDR in vivo.
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PMID:Daunorubicin-loaded magnetic nanoparticles of Fe3O4 overcome multidrug resistance and induce apoptosis of K562-n/VCR cells in vivo. 1991 66


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