Apoptosis Sensitization by Euphorbia Factor L1 in  ABCB1-Mediated Multidrug Resistant K562/ADR Cells

Zhang, Jianye; Lin, Min-Ting; Yi, Tao; Tang, Yiqun; Fan, Lan-Lan; He, Xi-Cheng; Zhao, Zhongzhen; Chen, Hubiao

doi:10.3390/molecules181012793

Cited by 24 publications

(24 citation statements)

References 33 publications

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“…Therefore, we examined the levels of P-gp protein in MDR and parental MCF-7 and K562 cells. Our data showed high P-gp protein levels in MCF-7/MDR and K562/MDR cells than the corresponding parental cells (Figure 1C ) and was consistent with the previous study [ 35 , 36 ]. Therefore, we selected MCF-7/MDR and K562/MDR cells to investigate if TTM reversed P-gp-mediated MDR.…”

Section: Resultssupporting

confidence: 93%

Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling

et al. 2017

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In this study, we investigated the mechanism by which tomentodione M (TTM), a novel natural syncarpic acid-conjugated monoterpene, reversed multi-drug resistance (MDR) in cancer cells. TTM increased the cytotoxicity of chemotherapeutic drugs such as docetaxel and doxorubicin in MCF-7/MDR and K562/MDR cells in a dose- and time-dependent manner. TTM reduced colony formation and enhanced apoptosis in docetaxel-treated MCF-7/MDR and K562/MDR cells, and it enhanced intracellular accumulation of doxorubicin and rhodamine 123 in MDR cancer cells by reducing drug efflux mediated by P-gp. TTM decreased expression of both P-gp mRNA and protein by inhibiting p38 MAPK signaling. Similarly, the p38 MAPK inhibitor SB203580 reversed MDR in cancer cells by decreasing P-gp expression. Conversely, p38 MAPK-overexpressing MCF-7 and K562 cells showed higher P-gp expression than controls. These observations indicate that TTM reverses MDR in cancer cells by decreasing P-gp expression via p38 MAPK inhibition.

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Section: Resultssupporting

confidence: 93%

Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling

et al. 2017

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“…Many chemotherapeutic agents exert anticancer activity by inducing apoptosis. Most chemotherapeutic agents applied in the treatment of hematologic malignancies can induce apoptosis, but MDR tumor cells are generally resistant to apoptosis induction [ 12 ]. Therefore, we investigated the apoptosis index in cisplatin-resistant gastric carcinoma cells expressing LV-E2F1-GFP.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the P-gp and MRP1 signaling pathways, apoptosis also mediates the killing effects of anticancer drugs, which is an important cause of MDR [ 12 ]. ZEB1 is a DNA-binding protein that binds to six consensus boxes located within the TAp73 promoter, resulting in the repression of TAp73 transcription [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of E2F1 in human gastric carcinoma is involved in anti-cancer drug resistance

et al. 2014

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BackgroundRoutine chemotherapy often cannot achieve good therapeutic effects because of multidrug resistance (MDR). MDR is frequently caused by the elevated expression of the MDR1 gene encoding P-glycoprotein (P-gp). E2F1 is a frequently overexpressed protein in human tumor cells that increases the activity of the MDR1 promoter, resulting in higher P-gp levels. The upregulation of P-gp might contribute to the survival of tumor cells during chemotherapy. E2F1 confers anticancer drug resistance; however, we speculate whether E2F1 affects MDR through other pathways. This study investigated the possible involvement of E2F1 in anticancer drug resistance of gastric carcinoma in vitro and in vivo.MethodsA cisplatin-resistant SGC7901/DDP gastric cancer cell line with stable overexpression of E2F1 was established. Protein expression levels of E2F1, MDR1, MRP, TAp73, GAX, ZEB1, and ZEB2 were detected by western blotting. The influence of overexpression of E2F1 on anticancer drug resistance was assessed by measuring IC50 of SGC7901/DDP cells to cisplatin, doxorubicin, and 5-fluorouracil, as well as the rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. We determined the in vivo effects of E2F1-overexpression on tumor size in nude mice, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining.ResultsThe SGC7901/DDP gastric cancer cell line stably overexpressing E2F1 exhibited significantly inhibited sensitivity to cisplatin, doxorubicin, and 5-fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells decreased after E2F1 upregulation, and that upregulation of E2F1 potentiated S phase arrest of the cell cycle. Furthermore, upregulation of E2F1 significantly decreased intracellular accumulation of doxorubicin. Western blot revealed that E2F1 upregulation suppressed expression of GAX, and increased the expression of MDR1, MRP, ZEB1, TAp73, and ZEB2.ConclusionsOverexpression of E2F1 promotes the development of MDR in gastric carcinoma, suggesting that E2F1 may represent an efficacious target for gastric cancer therapy.

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“…3D). Apoptosis is one of the most important mechanisms by which ADR (28)(29)(30)(31) and VCR (32,33) induce cancer cell death. Thus, we further demonstrated that treatment with ADR or VCR increased apoptotic rates in siMRUL-SGC7901/ADR and SGC7901/VCR cells compared with siNC groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

Long Noncoding RNA MRUL Promotes ABCB1 Expression in Multidrug-Resistant Gastric Cancer Cell Sublines

Wang

Zhang

et al. 2014

Molecular and Cellular Biology

131

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bMultidrug resistance (MDR) is the most common cause of chemotherapy failure in gastric cancer (GC) treatment; however, the underlying molecular mechanisms remain elusive. Long noncoding RNAs (lncRNAs) can be involved in carcinogenesis, but the effects of lncRNAs on MDR are poorly understood. We show here that the lncRNA MRUL (MDR-related and upregulated lncRNA), located 400 kb downstream of ABCB1 (ATP-binding cassette, subfamily B, member 1), was significantly upregulated in two multidrug-resistant GC cell sublines, SGC7901/ADR and SGC7901/VCR. Furthermore, the relative expression levels of MRUL in GC tissues were negatively correlated with in vitro growth inhibition rates of GC specimens treated with chemotherapeutic drugs and indicated a poor prognosis for GC patients. MRUL knockdown in SGC7901/ADR and SGC7901/VCR cells led to increased rates of apoptosis, increased accumulation, and reduced doxorubicin (Adriamycin [ADR]) release in the presence of ADR or vincristine. Moreover, MRUL depletion reduced ABCB1 mRNA levels in a dose-and time-dependent manner. Heterologous luciferase reporter assays demonstrated that MRUL might positively affect ABCB1 expression in an orientation-and position-independent manner. Our findings indicate that MRUL promotes ABCB1 expression and is a potential target to reverse the MDR phenotype of GC MDR cell sublines.T he development of multidrug resistance (MDR) followed by failure to respond to chemotherapy is a crucial problem in gastric cancer (GC) (1, 2). However, to date, the molecular mechanisms underlying MDR have not been fully elucidated.Chemotherapeutic drugs, such as doxorubicin (Adriamycin [ADR]) and vincristine (VCR), can induce Bax-and Bak-mediated apoptosis of tumor cells through DNA damage. Ribosomal protein (RP) S13 (RPS13) or RPL23 can promote MDR in gastric cancer cells by suppressing drug-induced apoptosis (3), while the activation of c-Jun N-terminal kinase 1 (JNK1) and caspase 3 (CPP32) is associated with enhancement of apoptosis in Baxtransfected gastric cancer cells (4). Among the MDR-related proteins, P-glycoprotein (P-gp), a 170-kDa transmembrane glycoprotein encoded by ABCB1, has been extensively studied (5-7). P-gp is an ATP-dependent efflux pump in the ATP-binding cassette (ABC) family and is expressed constitutively in the liver, kidney, intestine, brain, and many other tissues (5, 8). P-gp exhibits broad substrate specificity and is necessary for the elimination of intracellular toxic metabolic products or materials to maintain body homeostasis. Hence, P-gp can reduce intracellular chemotherapeutic drug concentrations by transporting cytotoxic agents out of the cell. P-gp upregulation often results in a compromised chemotherapy response and a worse prognosis for malignant tumor patients. However, the mechanism by which P-gp is upregulated remains unclear.Long noncoding RNAs (lncRNAs) refer to RNAs that lack coding potential, are Ͼ200 bp in length, and are responsible for at least 80% of all genome transcripts. lncRNAs play important roles in regulating t...

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Apoptosis Sensitization by Euphorbia Factor L1 in ABCB1-Mediated Multidrug Resistant K562/ADR Cells

Cited by 24 publications

References 33 publications

Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling

Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling

Overexpression of E2F1 in human gastric carcinoma is involved in anti-cancer drug resistance

Long Noncoding RNA MRUL Promotes ABCB1 Expression in Multidrug-Resistant Gastric Cancer Cell Sublines

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