Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-κB

Ghosh, Subrata; Wood, Charles; Boise, Lawrence H.; Mian, A. Mohsin; Deyev, Vadim; Feuer, Gerold; Toomey, Ngoc L.; Shank, Nicole C.; Cabral, Lisa; Barber, Glen N.; Harrington, William J.

doi:10.1182/blood-2002-08-2525

Cited by 88 publications

(63 citation statements)

References 38 publications

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“…Several in vitro studies have shown that inhibition of the NF-kB pathway could induce apoptosis in myeloma, lymphoma and leukemia patient cells and may be beneficial for the treatment of these malignancies. [150][151][152][153][154] Of particular interest are the clinical trials using the proteasome inhibitor PS-341 (VELCADE/bortezomib). Proteasome inhibition downregulates the NF-kB pathway and decreases the expression of IAPs and other antiapoptotic genes.…”

Section: Iaps As Targets For Cancer Therapymentioning

confidence: 99%

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Graaf

Witte²,

Jansen

2004

Leukemia

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Apoptosis is an essential process for the selection and survival of lymphocytes. Resistance to apoptosis can promote malignant transformation of hematopoietic cells. Proteins that regulate apoptosis may therefore be critically involved in the development of hematological cancer. A delicate balance between pro-and antiapoptotic mechanisms determines whether a cell death signal can activate the execution of the apoptotic cell death program. The family of inhibitor of apoptosis (IAP) proteins is a recently identified, novel category of apoptosis-regulatory proteins. IAPs can inhibit the activation of caspases that are the executioners of apoptosis, activated by both the extrinsic and intrinsic pathway. IAPs may thereby set the threshold for apoptosis-activation and play a key role in the regulation of apoptotic cell death. IAPs themselves are also subject to strict regulation through feedback mechanisms. This paper focuses on the role of IAP family proteins in the regulation of apoptosis and discusses implications for their involvement in cancer and possible use for cancer therapy, especially in leukemias and lymphomas.

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Section: Iaps As Targets For Cancer Therapymentioning

confidence: 99%

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Graaf

Witte²,

Jansen

2004

Leukemia

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“…2 In fact, drugs that inhibit NF-kB activation have exhibited considerable activity against PELs both in vitro and in vivo. [1][2][3] In addition, inhibition of NF-kB sensitizes PEL cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. 3 Recently, the proteasome inhibitor bortezomib (formerly PS-341) has demonstrated potent cytotoxicity across a wide variety of hematologic malignancies and solid tumors and received approval by the Food and Drug Administration (FDA) for the treatment of refractory multiple myeloma, where it has an acceptable toxicity profile.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] In addition, inhibition of NF-kB sensitizes PEL cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. 3 Recently, the proteasome inhibitor bortezomib (formerly PS-341) has demonstrated potent cytotoxicity across a wide variety of hematologic malignancies and solid tumors and received approval by the Food and Drug Administration (FDA) for the treatment of refractory multiple myeloma, where it has an acceptable toxicity profile. [4][5][6] By inhibiting the proteasome, which degrades proteins that are marked by ubiquitination, bortezomib modulates the cellular concentrations of hundreds of proteins that are involved in a wide variety of functions, including cell cycle progression, signal transduction, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas

Sun

Fisher

et al. 2004

Leukemia

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Primary effusion lymphomas (PELs) are a rare type of nonHodgkin's lymphoma that are resistant to cytotoxic chemotherapy. PELs manifest constitutive activation of nuclear factor kappa B (NF-jB), and inhibition of NF-jB induces apoptosis of PELs and sensitizes to tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-induced death. Bortezomib (PS-341), a peptidyl boronic acid inhibitor of the proteasome, is a potent agent against a wide range of hematologic malignancies and has been shown to inhibit NF-jB. Thus, we examined the cytotoxic effects of bortezomib alone and in combination with various drugs. Bortezomib potently inhibited NF-jB in PEL cells in a dose-dependent manner. In addition, bortezomib inhibited growth and induced apoptosis of PEL cell lines (IC 50 values of 3.4-5.0 nM). Results of drug interactions between bortezomib and chemotherapy (doxorubicin and Taxol) were scheduledependent: synergistic interactions were generally observed when PEL cells were pretreated with bortezomib prior to chemotherapy, whereas additive or even antagonistic interactions occurred with chemotherapy pretreatment or simultaneous treatment with bortezomib and chemotherapy. Most schedules of bortezomib and dexamethasone were synergistic, although pretreatment with dexamethasone resulted in additive interactions. Effects of combinations of bortezomib and TRAIL were generally additive. Thus, bortezomib represents a promising potential therapy for the treatment of PEL.

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“…As we have recently shown, LV-TRAIL particles contain the membrane-bound 42 kDa form of TRAIL, which is expressed in the 293 T producer cells upon transfection. 24 Thus, the residual apoptosis may be due to the TRAIL protein present in the viral particles, or due to the ability of AZT to sensitize for TRAIL-induced apoptosis, 32 or a combination of both. As both constructs express the marker gene GFP, we could measure the transduction efficiency of each construct by FACS analysis of GFP expression ( Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

“…This is in line with previous observations demonstrating that enveloped viruses with CD95-L or TRAIL transgenes carry these proteins on their surface, as a result from protein expression in the packaging cells. 24,37 Unfortunately, our attempt to further characterize this transduction-independent induction of cell death by AZT, an inhibitor of reverse transcriptase, was hampered, as this substance sensitizes for TRAIL-induced apoptosis (own observation, compare also Ghosh et al 32 ). Also, cells treated with AZT or ddC at concentrations required for inhibition of transduction underwent growth arrest after 5-7 days of culture (own data, not shown).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

Wenger

Mattern²,

Haas

et al. 2006

Cancer Gene Ther

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, which selectively induces apoptosis in many transformed cells without apparent toxic side effects in normal tissue. We recently described the construction and characterization of a lentiviral vector for expression of TRAIL. In this report, we evaluate its suitability for therapeutic application. In vitro, we observed specific induction of apoptosis upon transduction in human lung cancer cells. Cell death was partially dependent on successful integration and TRAIL expression by the vectors, but was to some extent mediated by protein carryover, as we found TRAIL protein associated with virus particles. Transduction of subcutaneously growing lung tumors on nude mice with lentiviral TRAIL mediated a transient suppression of tumor growth. Analysis of tumor sections revealed that transduction efficiency of lentiviral control vector but not of lentiviral TRAIL vector was high. This was because of the direct cytotoxic activity of recombinant TRAIL present in viral particles, which prevented efficient tumor transduction. These data therefore suggest that enveloped viral vectors constitutively expressing TRAIL are well suited for ex vivo applications, such as the transduction of tumorhoming cells, but may have a lower effect when used directly for the transduction of tumor cells in vivo.

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Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-κB

Cited by 88 publications

References 38 publications

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

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