Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

Nerini-Molteni, Silvia; Ferrarini, Marina; Cozza, Sara; Caligaris-Cappio, Federico; Sitia, Roberto

doi:10.1111/j.1365-2141.2008.07066.x

Cited by 65 publications

(63 citation statements)

References 47 publications

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“…Supporting this model, in myeloma cell lines (U266 and RPMI8226) and in myeloma patient specimens, antioxidants blunt bortezomib toxicity, and depletion of glutathione with buthionine sulfoximine (BSO) sensitizes cells to bortezomib-induced cell death (77). The same study shows that two markers of ER stress, induction of the transcription factors ATF4 and CHOP, occur after bortezomib exposure (77). ER stress as a consequence of proteasome inhibition has been demonstrated in a number of studies (70).…”

Section: Proteasome Inhibitorsmentioning

confidence: 87%

“…In head and neck squamous cell carcinoma cell lines, ROS and ER stress are implicated as major players in bortezomib cytotoxicity (29). Supporting this model, in myeloma cell lines (U266 and RPMI8226) and in myeloma patient specimens, antioxidants blunt bortezomib toxicity, and depletion of glutathione with buthionine sulfoximine (BSO) sensitizes cells to bortezomib-induced cell death (77). The same study shows that two markers of ER stress, induction of the transcription factors ATF4 and CHOP, occur after bortezomib exposure (77).…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

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Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Chandra

2009

Antioxidants & Redox Signaling

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The past decade has seen an exponential increase in the number of cancer therapies with defined molecular targets. Interestingly, many of these new agents are also documented to raise levels of intracellular reactive oxygen species (ROS) in addition to inhibiting a biochemical target. In most cases, the exact link between the primary target of the drug and effects on cellular redox status is unknown. However, it is important to understand the role of oxidative stress in promoting cytotoxicity by these agents, because the design of multiregimen strategies could conceivably build on these redox alterations. Also, drug resistance mediated by antioxidant defenses could potentially be anticipated and circumvented with improved knowledge of the redoxrelated effects of these targeted agents. Given the large number of targeted chemotherapies, in this review, we focus on selected agents that have shown promise in hematologic malignancies: proteasome inhibitors, histone deacetylase inhibitors, Bcl-2-targeted agents, and a kinase inhibitor called adaphostin. Despite structural differences within classes of these compounds, a commonality of causing increased oxidative stress exists, which contributes to induction of cell death. Antioxid. Redox Signal. 11, 1123-1137.

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Section: Proteasome Inhibitorsmentioning

confidence: 87%

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Chandra

2009

Antioxidants & Redox Signaling

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“…Our findings complement other studies that showed that modulation of antioxidant systems, glutathione and CuZnSOD, abrogates bortezomib resistance and resensitizes resistant myeloma cells to bortezomib. 15,35 Interestingly, despite higher Trx1 protein levels in bortezomib-resistant myeloma cells, 14 its inhibition using either a specific inhibitor PX-12 or Trx1 anti-sense plasmid did not sensitize bortezomibresistant U266 cells to bortezomib (data not shown). However, the underlying mechanism for this effect remains to be elucidated.…”

Section: Discussionmentioning

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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“…FtH is the active catalytic subunit of cytosolic ferritin and the most abundant ferritin subunit in MM cell lines as FtH/FtL ratio measured in MM.1S, KMS-18, RPMI-8226 and U266 was approximately 20:1 (data not shown). As MM cells are particularly sensitive to redox imbalance, 23 high ferritin levels may protect MM cells from bortezomib-induced ROS generation by limiting free iron availability. Interestingly,…”

Section: Ferritin and Bortezomib Sensitivitymentioning

confidence: 99%

Iron increases the susceptibility of multiple myeloma cells to bortezomib

et al. 2012

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ABSTRACTbeen reported following proteasome inhibition in cells treated with H 2 O 2 and nitric oxide generators. 13,14 Ferritin might undergo proteasomal degradation to recycle stored iron in cells pre-loaded with ferric ammonium citrate (FAC) 15 in conditions of decreased cell iron content 16,17 or in the presence of oxidative stress stimuli. 18 Here we report the analysis of iron metabolism and the effects of iron manipulation in MM cell lines and primary cells of patients treated with bortezomib. We observed that the basal iron storage capacity of MM cell lines directly correlates with bortezomib resistance and that bortezomib sensitizes MM cells to iron toxicity. Manipulation of iron homeostasis might be a tool to increase the susceptibility of MM cells to the effect of bortezomib and to overcome bortezomib resistance. Design and Methods Cell culture and cellular extractsCell culture media and reagents were from Invitrogen (Karlsruhe, Germany) and from Sigma-Aldrich (St. Louis, MO, USA). Bortezomib was purchased from LC Laboratories (Wobun, MA, USA). Patient-derived plasma cells were purified from bone marrow aspirates by density gradient centrifugation and then by CD138 immunomagnetic positive selection (Miltenyi Biotec, Bergisch Gladbach, Germany). Samples from Patient 2 were collected both at diagnosis (sample a) and relapse (sample b). Informed consent was obtained in accordance with the Declaration of Helsinki and the approval for use of primary samples was obtained from the Institutional Review Board of the San Raffaele Scientific Institute. MM cell lines and primary cells were cultured in RPMI medium supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin, 100 mg/mL streptomycin and 2 mM L-glutamine.Cellular extracts were prepared as described in the Online Supplementary Appendix. Iron manipulationsIron removal was obtained by addition of deferoxamine (DFO; Biofutura Pharma, Milan, Italy). Ferric ammonium citrate (FAC), holo-transferrin (FeTf) (Sigma-Aldrich) and N-acetyl Cysteine (NAC) (Sigma-Aldrich) were used for iron loading experiments. FAC and 55 FeAC were prepared by mixing FeCl 3 -HCl (Merk Millipore, Billerica, MA, USA) or 55 FeCl 3 -HCl (PerkinElmer, Monza, Italy) with citric acid at 1:2 ratios and then by adjusting pH to 7.4 with NH 4 OH.To estimate ferritin content in patients' cells, cellular extracts were incubated in vitro with a molar excess of 55 FeAC plus ascorbic acid. Then extracts were loaded without heating on sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and exposed to autoradiography. Cell viabilityCell viability was determined by measuring the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma-Aldrich). Briefly, cells were seeded in 96-well plates and assay performed on at least three wells for every condition. MTT was then added for 3 h at a final concentration of 0.25 mg/mL. Plates were centrifuged at 3200g for 5 min and the soluble fraction decanted. Crystal pellets were suspended in DMSO a...

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Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

Cited by 65 publications

References 47 publications

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

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

Iron increases the susceptibility of multiple myeloma cells to bortezomib

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