Overexpression of MDR1 and survivin, and decreased Bim expression mediate multidrug-resistance in multiple myeloma cells

Tsubaki, Masanobu; Satou, Takao; Itoh, Tatsuki; Imano, Motohiro; Komai, Makiko; Nishinobo, Minori; Yamashita, Megumi; Yanae, Masashi; Yamazoe, Yuzuru; Nishida, Shozo

doi:10.1016/j.leukres.2012.07.003

Cited by 66 publications

(48 citation statements)

References 36 publications

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“…17 However, bortezomib also increases constitutive NF-kb expression levels by activating IKKb, leading to NF-kb nuclear translocation and the transcription of multiple NFkb-regulated genes including Survivin, and Cyclin D1, which are associated with multi-drug resistance in MM. [18][19][20] This upregulation of NF-kb expression and its signaling pathway has been associated with acquisition of bortezomib resistance due to prolonged drug exposure in MM. 13,18 However, the role of the NF-kb signaling pathway in hypoxia-induced bortezomib resistance in MM is unknown.…”

Section: Introductionmentioning

confidence: 99%

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

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Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxicmyeloma cells to bortezomib. Hypoxia increased NF-kb subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-kb p65 protein levels in the nucleus and reduced the expression of NF-kb-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the na€ ıve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-kb-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-kb signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomibresistance and improve survival outcomes of MM patients.

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Section: Introductionmentioning

confidence: 99%

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

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“…Notably, survivin is always co-overexpressed with other drugresistant molecules such as P-gp in drug-resistant cancer cells [28]. Recent study shows that YM155, the first-class of survivin inhibitor, is a substrate of P-gp, indicating that YM155 may not be able to exert its full potential in cancer patients with P-gp-mediated drug resistance after long-term chemotherapy [113].…”

Section: Discussionmentioning

confidence: 99%

“…P-glycoprotein (P-gp) and survivin are always cooverexpressed in drug-resistant cancer cells [28], and survivin transcription is associated with P-gp overexpression [29]. Patients with acute myeloid leukemia (AML) who exhibit an upregulation in the transcription of MDR1 and survivin mRNA also show poor therapeutic response and survival [30].…”

Section: Role Of Survivin In Cancer Drug Resistancementioning

confidence: 99%

Nanoparticle-mediated inhibition of survivin to overcome drug resistance in cancer therapy

Wang

Chan

et al. 2016

Journal of Controlled Release

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“…Survivin has been reported to be overexpressed ubiquitously in cells in several types of cancer, including breast cancer (43), lung cancer (44) and MM (45). Furthermore, elevated levels of survivin have been correlated with poor prognosis, decreased survival and chemotherapy resistance in MM cells (45,46). Accordingly, the inhibition of survivin may be an efficient form of therapy in patients with MM.…”

Section: Discussionmentioning

confidence: 99%

Aspirin enhances the cytotoxic activity of bortezomib against myeloma cells via suppression of Bcl-2, survivin and phosphorylation of AKT

Ding

Chen

2016

Oncology Letters

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In our previous study, it was found that aspirin (ASA) exerted antimyeloma actions in vivo and in vitro. The resistance to bortezomib (BTZ) in multiple myeloma (MM) is partly due to AKT activation and the upregulation of survivin induced by BTZ, which are the targets of ASA in gastric and ovarian cancer, respectively. Thus, the present study investigated the interaction between ASA and BTZ in MM and further clarified the underlying mechanisms. MM1.S and RPMI-8226 cell lines harboring the N- and K-Ras mutations, respectively, were treated with 2.5 mM ASA, 10 nM BTZ and ASA+BTZ for different durations. The proliferation and apoptosis of the cells were determined, and the underlying mechanisms governing the interaction of ASA and BTZ were examined in the MM cells. Treatment with ASA+BTZ caused higher rates of proliferative inhibition and apoptosis in the MM1.S and RPMI-8226 cells in time-dependent manner, compared with either agent alone. A drug interaction assay revealed the additive effect of ASA and BTZ on the myeloma cells. ASA alone inhibited the levels of phosphorylated AKT (p-AKT) and survivin, whereas BTZ alone augmented the levels of p-AKT and survivin. Of note, ASA markedly decreased the upregulation of p-AKT and survivin induced by BTZ. Treatment with ASA+BTZ significantly suppressed the level of Bcl-2, compared with either agent alone. ASA may potentiate the antimyeloma activity of BTZ against myeloma cells via suppression of AKT phosphorylation, survivin and Bcl-2, indicating the potential of ASA+BTZ in treating MM, particularly for cases of BTZ-refractory/relapsed MM.

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Overexpression of MDR1 and survivin, and decreased Bim expression mediate multidrug-resistance in multiple myeloma cells

Cited by 66 publications

References 36 publications

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

Nanoparticle-mediated inhibition of survivin to overcome drug resistance in cancer therapy

Aspirin enhances the cytotoxic activity of bortezomib against myeloma cells via suppression of Bcl-2, survivin and phosphorylation of AKT

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