The resistance mechanisms of proteasome inhibitor bortezomib

Lu, Sangwei; Wang, Jianmin

doi:10.1186/2050-7771-1-13

Cited by 127 publications

(79 citation statements)

References 52 publications

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“…Because proteasome inhibitors induce cancer cell death via the induction of proteotoxicity, oxidative stress, and ER stress, some of these agents are considered anticancer drugs (4)(5)(6). For example, BTZ (also known as Velcade or PS-341) and CFZ have been approved by the FDA for the treatment of patients with mantle cell lymphoma (MCL) and multiple myeloma (7)(8)(9). However, differential sensitivities to BTZ were observed among cancer cell lines, though the lines were derived from the same tissues (9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Mimura

Okada

et al. 2014

Molecular and Cellular Biology

166

153

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The ubiquitin-proteasome pathway degrades ubiquitinated proteins to remove damaged or misfolded protein and thus plays an important role in the maintenance of many important cellular processes. Because the pathway is also crucial for tumor cell growth and survival, proteasome inhibition by specific inhibitors exhibits potent antitumor effects in many cancer cells. xCT, a subunit of the cystine antiporter system x c ؊ , plays an important role in cellular cysteine and glutathione homeostasis. Several recent reports have revealed that xCT is involved in cancer cell survival; however, it was unknown whether xCT affects the cytotoxic effects of proteasome inhibitors. In this study, we found that two stress-inducible transcription factors, Nrf2 and ATF4, were upregulated by proteasome inhibition and cooperatively enhance human xCT gene expression upon proteasome inhibition. In addition, we demonstrated that the knockdown of xCT by small interfering RNA (siRNA) or pharmacological inhibition of xCT by sulfasalazine (SASP) or (S)-4-carboxyphenylglycine (CPG) significantly increased the sensitivity of T24 cells to proteasome inhibition. These results suggest that the simultaneous inhibition of both the proteasome and xCT could have therapeutic benefits in the treatment of bladder tumors.

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mentioning

confidence: 99%

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Mimura

Okada

et al. 2014

Molecular and Cellular Biology

166

153

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“…21 Conversely, however, bortezomib also enhances 'constitutive' levels of NF-kB through activation of IKKb, ultimately leading to NF-kB nuclear translocation and the transcription of multiple NF-kB-induced genes, including Bruton's tyrosine kinase (BTK). 22 BTK, a non-receptor tyrosine kinase, is now known to be of key importance to a number of haematological malignancies, including MM, 23 chronic lymphocytic leukemia (CLL) 24 and acute myeloid leukemia (AML).…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

et al. 2015

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Abbreviations: MM -multiple myeloma; PI -proteasome inhibitor; NF-kB -nuclear factor-kappa B; BMSC -bone marrow stromal cells; BTK -Bruton's tyrosine kinase.Multiple Myeloma (MM) is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last 10-15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. To model bortezomib-resistant MM we generated bortezomib-resistant MM cell lines (n D 4 ) and utilised primary malignant plasma cells from patients relapsing after bortezomib treatment (n D 6 ). We identified enhanced Bruton's tyrosine kinase (BTK) activity in bortezomib-resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib (0.5 mM) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5 nM). Further analysis of pro-survival signaling revealed a role for the NF-kB p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-kB p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-kB p65 interference, also restored sensitivity to bortezomib, significantly reducing cell viability (37.5 § 6 .9 %, ANOVA P 0 .001). Accordingly, we propose the clinical evaluation of a bortezomib/ibrutinib combination therapy, including in patients resistant to single-agent bortezomib.

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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.…”

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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The resistance mechanisms of proteasome inhibitor bortezomib

Cited by 127 publications

References 52 publications

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

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

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