Proteasome inhibitor bortezomib-induced apoptosis in natural killer (NK)–cell leukemia and lymphoma: an in vitro and in vivo preclinical evaluation

Shen, Liangliang; Au, Wing‐Yan; Guo, Tianhuan; Wong, Kai-Yau; Wong, Matthew; Tsuchiyama, Junjiro; Yuen, Po Wing; Kwong, Yok–Lam; Liang, Raymond; Srivastava, Gopesh

doi:10.1182/blood-2007-02-072900

Cited by 37 publications

(21 citation statements)

References 8 publications

(7 reference statements)

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“…1A). Similar data from the NK-YS cell line and primary lymphoma cells have been reported by our group (14). The MTS assay was repeated in this study to compare with the data from the SNK-6 cell line.…”

Section: Snk-6 Cells Were Less Sensitive To Bortezomib Than Nk-ys Andsupporting

confidence: 58%

“…We have described previously constitutive activation of nuclear factor-nB in NK-cell lymphoma (13). Given the involvement of nuclear factornB with tumorigenesis and the action of bortezomib against nuclear factor-nB (11), we have recently investigated and reported its therapeutic potential for NK-cell neoplasms (14). In this study, we have examined the molecular mechanisms of bortezomib-induced cell death in NK lymphoma cell lines and primary lymphoma cells.…”

Section: Introductionmentioning

confidence: 99%

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Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells

Shen¹,

Wong³

et al. 2008

Molecular Cancer Therapeutics

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The proteasome inhibitor bortezomib (PS-341/Velcade) is used for the treatment of relapsed and refractory multiple myeloma and mantle-cell lymphoma. We recently reported its therapeutic potential against natural killer (NK)-cell neoplasms. Here, we investigated the molecular mechanisms of bortezomib-induced cell death in NK lymphoma cells. NK lymphoma cell lines (SNK-6 and NK-YS) and primary cultures of NK lymphomas treated with bortezomib were examined for alterations in cell viability, apoptosis, cellular senescence, and cell cycle status. Bortezomib primarily induced mitochondrial apoptosis in NK-YS cells and in primary lymphoma cells at the same concentration as reported in myeloma cells. Unexpectedly, SNK-6 cells required a significantly higher median inhibitory concentration of bortezomib (23 nmol/L) than NK-YS and primary lymphoma cells (6-13 nmol/L). Apoptosis was limited in SNK-6 cells due to the extensively delayed turnover of Bcl-2 family members. These cells were killed by bortezomib, albeit at higher pharmacologic concentrations, via mitotic catastrophe-a mitotic cell death associated with M-phase arrest, cyclin B1 accumulation, and increased CDC2/CDK1 activity. Our results suggest that, in addition to cell death by apoptosis at lower bortezomib concentrations, NK lymphoma cells resistant to bortezomib-induced apoptosis can be killed via mitotic catastrophe, an alternative cell death mechanism, at higher pharmacologic concentrations of bortezomib. Hence, activating mitotic catastrophe by bortezomib may provide a novel therapeutic approach for treating apoptosis-resistant NK-cell malignancies and other cancers. [Mol Cancer Ther 2008;7(12):3807 -15]

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Section: Snk-6 Cells Were Less Sensitive To Bortezomib Than Nk-ys Andsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells

Shen¹,

Wong³

et al. 2008

Molecular Cancer Therapeutics

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“…Another important anticancer mechanism occurs via upregulation of NOXA, which is a pro-apoptotic protein that may interact with the anti-apoptotic proteins of the B-cell lymphoma 2 (Bcl-2) subfamily, leading to the apoptotic death of malignant cells. Bortezomib-induced apoptosis has been demonstrated in T and NK lymphoma cells, implying that bortezomib may have a significant therapeutic role in the treatment of T-cell lymphoma (25)(26)(27).…”

Section: Ptcl-nos Ctclmentioning

confidence: 99%

Bortezomib-based chemotherapy to treat refractory angioimmunoblastic T-cell lymphoma: A case report and review of the literature

Yang

Zhang

2016

Oncology Letters

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Abstract. The peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive neoplasms that account for <15% of all non-Hodgkin's lymphoma cases in adults. Angioimmunoblastic T-cell lymphoma (AITL) is a specific subtype of PTCL. The tumor is frequently aggressive and there is currently no general consensus regarding an effective treatment strategy. The present study reports a case in which bortezomib combined with dexamethasone was used to treat refractory AITL. A 63-year-old woman was admitted to Sir Run Run Shaw Hospital, Zhejiang University School of Medicine (Zhejiang, China) on August 17, 2013. The patient had been diagnosed with AITL for 4 months and had experienced a relapse of symptoms for the 4 days prior to admission. The patient demonstrated fever and dyspnea, accompanied by severe edema in the face and lower limbs, which later spread to the right upper limb. The patient was treated with bortezomib plus dexamethasone, which rapidly relieved the symptoms. The patient was subsequently administered an additional 2 cycles of bortezomib-based chemotherapy and survived for an additional 4 months, prior to succumbing to the disease. Only a small number of studies have reported the use of bortezomib in the treatment of T-cell lymphoma. The present study suggested that bortezomib-based treatment may be a reliable, safe and effective alternative for the treatment of relapsed/refractory PTCL. The efficacy of bortezomib as a treatment for PTCL requires additional evaluation in future studies.

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“…Good responses to a RAS farnesyltransferase inhibitor, tipifarnib have been obtained in patients with symptomatic T-LGL leukemia and CLPD-NK, in accordance with the findings of constitutively active signaling of the Ras/MAPK/ERK pathway. 29 In addition, the proteasome inhibitor bortezomib has been reported to display anticancer activity against aggressive NK leukemia and extranodal NK/T cell lymphoma 48 opening new therapeutic perspectives for patients with these diseases. Recent evidence that dasatinib, a broad-spectrum tyrosine kinase inhibitor currently used for treatment of Philadelphia chromosomepositive leukemias, induces a significant expansion of LGL cells highlights the relevance of signaling pathways in the pathogenesis of LGL disorders.…”

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confidence: 99%

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

Zambello¹,

Semenzato²

2009

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o nhaplotype with a higher frequency than the normal population, as occurs in patients with rheumatoid arthritis. In recent years progress has been made in understanding the mechanisms sustaining T-LGL leukemia and CLPD-NK. It is now becoming evident that the phenotype of T-cell LGL leukemia is consistent with that of fully differentiated cytotoxic T lymphocytes. The hallmark of T-LGL leukemia lymphocytes is the failure to undergo activation-induced cell death (AICD), this event being consequent to a critical impairment of apoptotic pathways. T-LGL leukemia is characterized by an abnormal clonal expansion of antigen-primed mature cytotoxic T-lymphocytes (CTL) which successfully escape AICD and remain competent in the long-term. 10 Clearance of potentially harmful antigen-stimulated effector cytotoxic T-cells after a successful immune response occurs physiologically by triggering Fas-mediated apoptosis through induction of a death-inducing signaling complex (DISC). This process, which is crucial to T-cell homeostasis, requires fine tuning between proliferation, survival, and apoptosis. Like normal activated CTL, leukemic T-LGL cells exhibit activation of multiple survival signaling pathways. 6 However, unlike normal activated CTL, leukemic T-LGL cells are not sensitive to Fas-induced apoptosis, 20 a process that is essential for AICD. 21 Fas resistance can occur in cells with overexpression of the DISC inhibitory protein c-FLIP. This latter is constitutively expressed in leukemic LGL and prevents DISC formation and Fas-mediated apoptosis. 22 Several genes are likely to be involved in the above mentioned processes and gene expression profiling has revealed that leukemic LGL are characterized by the expression of genes affecting apoptosis, regulation of TCR signaling and immune response. 23 This supports the view that an uncoupling of activation and apoptotic pathways is responsible for the failure of AICD. In fact, genes that are up-regulated in leukemic LGL have antiapoptotic functions whereas those that are down-regulated are pro-apoptotic. Pathway-based microarray analysis also indicated that the balance of pro-apoptotic (ceramide and its analogs) and anti-apoptotic (sphingosine-1-phosphate, S1P) sphingolipid-mediated signaling is deregulated in leukemic LGL in favor of S1P. 23 Of great interest is the model suggesting that the persistence of interleukin-15 and platelet-derived growth factor is sufficient to reproduce all known deregulations in leukemic T-LGL. 10 Interleukin-15 alters expression of Bcl-2 family members, i.e. Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1. Genes belonging to the BCL-2 family, such as the BCL-2 related X gene (BAX) are down-regulated, while the myeloid cell factor (MCL-1) is up-regulated. In primary leukemic LGL, Bid (which is down-regulated by interleukin-15) levels are low but are reversed following bortezomib treatment, with subsequent increases in LGL apoptosis. These data provide a novel molecular mechanism for interleukin-15 control of Bid whi...

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Proteasome inhibitor bortezomib-induced apoptosis in natural killer (NK)–cell leukemia and lymphoma: an in vitro and in vivo preclinical evaluation

Cited by 37 publications

References 8 publications

Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells

Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells

Bortezomib-based chemotherapy to treat refractory angioimmunoblastic T-cell lymphoma: A case report and review of the literature

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

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