Antitumor Activity of Bortezomib Alone and in Combination with Trail in Human Acute Myeloid Leukemia

Conticello, Concetta; Adamo, Luana; Vicari, Luisa; Giuffrida, Raffaella; Iannolo, Gioacchin; Anastasi, Gabriele; Caruso, L; Moschetti, Gaetano; Cupri, Alessandra; Palumbo, Giuseppe A.; Gulisano, Massimo; Maria, Ruggero De; Giustolisi, Rosario; Raimondo, Francesco Di

doi:10.1159/000151511

Cited by 27 publications

(11 citation statements)

References 50 publications

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“…However, AML is largely resistant to TRAIL-induced apoptosis, due to inhibition or lack of expression of the apoptosis-inducing TRAIL receptors (DR4, DR5) and overexpression of intracellular anti-apoptotic factors, such as c-FLIP [33]. There is a strong rationale for using bortezomib to overcome TRAIL resistance based on the known influence of bortezomib on the proteins regulating the TRAIL apoptotic pathway, however, currently there is limited information on the potential of bortezomib to sensitize AML to rhTRAIL [38]. Our data reveal that bortezomib exerts potent pro-apoptotic effects against AML in vitro in the nanomolar range and also sensitizes AML cells of myelomonocytic/monocytic phenotype, which account for 20-30% of AML cases [39], to rhTRAIL, an effect which is at least partly mediated by inhibition of NF-κB and by reducing c-FLIP and XIAP expression, which is consistent with similar findings in other cancer cells [30,40-42].…”

Section: Resultsmentioning

confidence: 99%

The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

Dijk

Murphy

Morrell

et al. 2011

Cancers

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Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL.

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Section: Resultsmentioning

confidence: 99%

The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

Dijk

Murphy

Morrell

et al. 2011

Cancers

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“…Earlier studies also suggested that bortezomib could dramatically sensitize not only multiple myeloma cells (3), but also a variety of human and mouse solid tumor cells to the apoptotic effects of TRAIL in vitro (4, 5). Subsequent studies confirmed that a combination of bortezomib with TRAIL could overcome the resistance to TRAIL cytotoxicity in vitro in a wide variety of cancer cells including leukemias and lymphomas (6, 7), prostate (8, 9), colon (5), bladder (8), thyroid (10), ovarian (11), lung (12), sarcoma (13), hepatoma (14, 15) and glioma (16). Encouragingly, normal cells still seem to remain relatively resistant to TRAIL, even in combination with bortezomib (14, 15).…”

Section: Introductionmentioning

confidence: 88%

Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex

Brooks

Jacobsen

et al. 2010

Molecular Cancer Research

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Bortezomib (VELCADE) could sensitize certain human renal cell carcinoma (RCC) lines to the apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Analysis of seven human RCC showed a clear increase in the sensitivity of four of the RCC to TRAIL cytotoxicity following bortezomib (5-20 nmol/L) treatment, whereas the remaining three remained resistant. Tumor cell death following sensitization had all the features of apoptosis. The enhanced antitumor activity of the bortezomib and TRAIL combination was confirmed in long-term (6 days) cancer cell outgrowth assays. The extent of proteasome inhibition by bortezomib in the various RCC was equivalent. Following bortezomib treatment, neither changes in the intracellular protein levels of various Bcl-2 and IAP family members, nor minor changes in expression of TRAIL receptors (DR4, DR5), correlated well with the sensitization or resistance of RCC to TRAIL-mediated apoptosis. However, enhanced procaspase-8 activation following bortezomib pretreatment and subsequent TRAIL exposure was only observed in the sensitized RCC in both cell extracts and death-inducing signaling complex immunoprecipitates. These data suggest that the molecular basis for bortezomib sensitization of RCC to TRAIL primarily involves early amplification of caspase-8 activity. In the absence of this increased caspase-8 activation, other bortezomib-induced changes are not sufficient to sensitize RCC to TRAIL-mediated apoptosis. Mol Cancer Res; 8(5); 729-38. ©2010 AACR.

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“…Conticello et al [115] examined the sensitivity of bone marrow cells from AML patients (34 patients; 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combinaton with TRAIL, a member of the tumor necrosis factor (TNF) family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from all 34 AML patients.…”

Section: Antitumor Activity Of Bortezomib In Combination With Trail Imentioning

confidence: 99%

Antiproliferative and Proapoptotic Effects of Proteasome Inhibitors and their Combination with Histone Deacetylase Inhibitors on Leukemia Cells

Fuchs¹,

Provazníková²,

Marinov³

et al. 2009

CHDDT

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New chemotherapeutic agents are still required to further optimise treatment of leukemia patients. Proteasome inhibition by bortezomib, PR-171 (carfilzomib) and NPI-0052 (salinosporamide A) has been successfully used for the treatment of multiple myeloma and mantle cell lymphoma and is considered also as novel treatment strategy in leukemia. Combination of proteasome inhibitors bortezomib and NPI-0052 induces synergistic anti-multiple myeloma activity both in vitro using multiple myeloma cells and in vivo in a human plasmacytoma xenograft mouse model. Cell death resulting from proteasome inhibition requires caspase activation and increased levels of reactive oxygen species. While bortezomib induces several caspases, NPI-0052 activates predominantly caspase-8-dependent pathway. We studied the effect of bortezomib (10 nM) on DNA synthesis and apoptosis in human acute myeloid cell lines KASUMI-1, ML-1, ML-2 and CTV-1 cells. Bortezomib was potent inhibitor of DNA synthesis in all four types of leukemia cells and induced apoptosis in KASUMI-1, ML-2 and CTV-1 cells but not in ML-1 cells. Other research groups showed that histone deacetylase inhibitors (valproic acid or benzamide derivative MS-275) in combination with NPI-0052 or PR-171 induced greater levels of acute leukemia cell death than in combination with bortezomib. Proteasome inhibition as monotherapy and its combination with many conventional therapies as novel treatment strategies in leukemia are promising. Malignant cells are more sensitive to this treatment than normal hematopoietic cells.

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Antitumor Activity of Bortezomib Alone and in Combination with Trail in Human Acute Myeloid Leukemia

Cited by 27 publications

References 50 publications

The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex

Antiproliferative and Proapoptotic Effects of Proteasome Inhibitors and their Combination with Histone Deacetylase Inhibitors on Leukemia Cells

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