Differential expression and response to arsenic stress of MRPs and ASAN1 determine sensitivity of classical multidrug-resistant leukemia cells to arsenic trioxide

Chen, Jing; Cheng, Jie; Yi, Juan; Xie, Baohua; Lin, Li; Liu, Zhuan; Zhao, Huaishun; Wang, Bei; Ai, Ziying; Yang, Yue; Wei, Hulai

doi:10.1016/j.leukres.2016.10.003

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…A cell viability assay was performed as previously described (24). Briefly, cells were plated in 96-well plates at an initial density of 4×10 3 cells/well and cultured overnight.…”

Section: Methodsmentioning

confidence: 99%

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Benzyl isothiocyanate suppresses development and metastasis of murine mammary carcinoma by regulating the Wnt/β‑catenin pathway

Xie

Жао²,

Guo

et al. 2019

Mol Med Report

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Benzyl isothiocyanate (BITC) has been reported to exhibit antitumor properties in various cancer types; however, the underlying mechanisms of its action remain unclear. In the present study, the efficacy of BITC on murine mammary carcinoma cells was evaluated in vitro and in vivo , revealing a potential mechanism for its action. In vivo bioluminescence imaging indicated dynamic inhibition of murine mammary carcinoma cell growth and metastasis by BITC. A terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay demonstrated that BITC also induced apoptosis. BITC further exhibited antitumorigenic activity in 4T1-Luc cells in vitro via the inhibition of cell proliferation, induction of apoptosis and cell cycle arrest, and inhibition of cell migration and invasion. Furthermore, the activity of key molecules of the adenomatous polyposis coli (APC)/β-catenin complex was altered following treatment with BITC, which suggested a potential role for the APC/β-catenin complex in the BITC-mediated induction of apoptosis and inhibition of metastasis in murine mammary carcinoma. BITC upregulated the activity of glycogen synthase kinase-3β and APC proteins, whereas it downregulated β-catenin expression. The inhibition of metastasis was accompanied with the downregulation of vimentin and upregulation of E-cadherin. Conversely, BITC did not exhibit toxicity or side effects in the normal mammary epithelial cell line MCF-10A. The present study indicated that BITC exhibited anticancer properties due to the induction of breast cancer cell apoptosis and inhibition of breast cancer cell metastasis mediated by the Wnt/β-catenin signaling pathway.

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“…A cell viability assay was performed as previously described (24). Briefly, cells were plated in 96-well plates at an initial density of 4×10 3 cells/well and cultured overnight.…”

Section: Methodsmentioning

confidence: 99%

“…RNA isolation and RT-qPCR were performed as previously described (24). Total RNA from the cells was isolated using TRIzol ® reagent (Invitrogen; Thermo Fisher Scientific, Inc.) and reverse transcribed to cDNA using a PrimeScript RT reagent kit purchased from Takara Bio, Inc. according to the manufacture's protocol.…”

Section: Methodsmentioning

confidence: 99%

Benzyl isothiocyanate suppresses development and metastasis of murine mammary carcinoma by regulating the Wnt/β‑catenin pathway

Xie

Жао²,

Guo

et al. 2019

Mol Med Report

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“…Other ATP-binding cassette (ABC) transporters than P -glycoprotein might be more important for As 2 O 3 . Treatment with As 2 O 3 lead to the induction of ABCC1, but not P -glycoprotein ( Seo et al, 2007 ) and As 2 O 3 -resistant cell lines overexpressed P -glycoprotein but also ABCC1, ABCC2, and ABCC4 ( Chen et al, 2009 , 2016 ; Yuan et al, 2016 ). ABCC1-overexpressing tumor cells accumulated less As 2 O 3 than wild-type cells ( Salerno and Garnier-Suillerot, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology

2018

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Arsenic trioxide is a traditional remedy in Chinese Medicine since ages. Nowadays, it is clinically used to treat acute promyelocytic leukemia (APL) by targeting PML/RARA. However, the drug’s activity is broader and the mechanisms of action in other tumor types remain unclear. In this study, we investigated molecular modes of action by classical and network pharmacological approaches. CEM/ADR5000 resistance leukemic cells were similar sensitive to As2O3 as their wild-type counterpart CCRF-CEM (resistance ratio: 1.88). Drug-resistant U87.MG ΔEGFR glioblastoma cells harboring mutated epidermal growth factor receptor were even more sensitive (collateral sensitive) than wild-type U87.MG cells (resistance ratio: 0.33). HCT-116 colon carcinoma p53-/- knockout cells were 7.16-fold resistant toward As2O3 compared to wild-type cells. Forty genes determining cellular responsiveness to As2O3 were identified by microarray and COMPARE analyses in 58 cell lines of the NCI panel. Hierarchical cluster analysis-based heat mapping revealed significant differences between As2O3 sensitive cell lines and resistant cell lines with p-value: 1.86 × 10-5. The genes were subjected to Galaxy Cistrome gene promoter transcription factor analysis to predict the binding of transcription factors. We have exemplarily chosen NF-kB and AP-1, and indeed As2O3 dose-dependently inhibited the promoter activity of these two transcription factors in reporter cell lines. Furthermore, the genes identified here and those published in the literature were assembled and subjected to Ingenuity Pathway Analysis for comprehensive network pharmacological approaches that included all known factors of resistance of tumor cells to As2O3. In addition to pathways related to the anticancer effects of As2O3, several neurological pathways were identified. As arsenic is well-known to exert neurotoxicity, these pathways might account for neurological side effects. In conclusion, the activity of As2O3 is not restricted to acute promyelocytic leukemia. In addition to PML/RARA, numerous other genes belonging to diverse functional classes may also contribute to its cytotoxicity. Network pharmacology is suited to unravel the multifactorial modes of action of As2O3.

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“…A cell viability assay was performed as previously described [30]. Briefly, cells in exponential growth phase were plated at a final concentration of 1 × 10 4 cells/well into 96-well culture plates.…”

Section: Cell Viability Assaymentioning

confidence: 99%

MicroRNA-1246 by Targeting AXIN2 and GSK-3β Overcomes Drug Resistance and Induces Apoptosis in Chemo-resistant Leukemia Cells

Xie¹,

Li²,

Zhang³

et al. 2021

J. Cancer

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Background and objective: Chemotherapy plays an important role in the treatment of leukemia. Multidrug resistance (MDR) induced by chemotherapy always leads to treatment failure and disease recurrence. MicroRNAs (miRNAs) have been verified as crucial components in carcinogenesis, including chemo-resistance of tumor cells, which has not been fully understood. In this study, we aimed to identify the potential candidate miRNA, miR-1246, and reveal its regulatory role in chemo-resistance of leukemia cells. Methods: Candidate miRNAs were selected by microarray analysis, screened by bioinformatics tools and verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Chemo-resistant phenotypes, including cell viability, apoptosis, adriamycin (ADM) efflux and in vivo oncogenicity of leukemia cells following transfected with miR-1246 mimics or inhibitor were checked with or without ADM treatment to make clear the relationship between miR-1246 and chemo-resistance. RT-qPCR, western blot and dual luciferase reporter assay were performed to measure the expression of related genes and address the potential regulatory mechanism of miR-1246 in chemo-resistance. Results: The expression of miR-1246 was significantly higher in chemo-resistant leukemia K562/ADM cells, HL-60/RS cells and recurrent primary leukemia cells. Loss of miR-1246 inhibited proliferation, induced apoptosis, altered cell cycle distribution, inhibited ADM efflux in chemo-resistant leukemia cells, while overexpression of miR-1246 showed the opposite role in chemo-sensitive leukemia cells. Both bioinformatics prediction and luciferase assay indicated that AXIN2 and glycogen synthase kinase 3 beta (GSK-3β) were the direct targets of miR-1246 in leukemia cells. Inhibition of miR-1246 could up-regulate AXIN2 and GSK-3β and inactivate Wnt/β-catenin pathway, accompanied with inhibiting the expression of β-catenin and further influencing the expression of P-glycoprotein (P-gp) in the chemo-resistant leukemia cells. Conclusions: Chemo-resistant ability of MDR leukemia cells is attenuated by loss of miR-1246 via negatively regulating AXIN2 and GSK-3β to inactivate Wnt/β-catenin pathway and suppress P-gp expression, these mean that targeting miR-1246-AXIN2/GSK-3β-Wnt/β-catenin axis may be beneficial to overcome the chemo-resistance in relapse and refractory leukemia patients.

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Differential expression and response to arsenic stress of MRPs and ASAN1 determine sensitivity of classical multidrug-resistant leukemia cells to arsenic trioxide

Cited by 8 publications

References 28 publications

Benzyl isothiocyanate suppresses development and metastasis of murine mammary carcinoma by regulating the Wnt/β‑catenin pathway

Benzyl isothiocyanate suppresses development and metastasis of murine mammary carcinoma by regulating the Wnt/β‑catenin pathway

Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology

MicroRNA-1246 by Targeting AXIN2 and GSK-3β Overcomes Drug Resistance and Induces Apoptosis in Chemo-resistant Leukemia Cells

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