Phase II Clinical Experience With the Novel Proteasome Inhibitor Bortezomib in Patients With Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma

Glucocorticoids induce apoptosis in chronic lymphocytic leukemia (CLL) cells through a caspase-dependent mechanism. However, their mechanism of action remains unknown. We have studied the regulation of the proapoptotic BH3-only Bcl-2 interacting mediator of cell death (BIM) in CLL cells. We demonstrate that glucocorticoids upregulate BIM at protein and mRNA levels. We have investigated the ability of different survival signals, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), stromal cell-derived factor-1a (SDF-1a), interleukin 4 (IL-4) and B-cell receptor (BCR) activation, to influence the levels of BIM and its induction by glucocorticoids. TPA downregulates BIM EL by extracellular signal-regulated kinase (ERK)-mediated BIM phosphorylation and further proteasomemediated degradation. However, SDF-1a and BCR activation induce transient BIM phosphorylation, without protein degradation. Proteasome inhibitors do not modify the levels of BIM with respect to untreated cells. However, they induce apoptosis and inhibit TPA-induced BIM EL degradation, leading to its accumulation. In conclusion, the results implicate BIM in glucocorticoid-induced apoptosis in CLL cells. BIM EL phosphorylation through the ERK pathway targets the protein for proteasomal degradation.

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“…Thus, BIM could be involved in the mechanism of action of bortezomib, which inhibits proteasome and is used in CLL treatment. 53 …”

Section: Discussionmentioning

confidence: 99%

Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells

et al. 2006

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“…Pharmacological inhibitors of the proteasome have recently received much attention in the light of their potent antitumor activity [1,2]. In this setting, bortezomib (Velcade) was demonstrated to be effective in the treatment of multiple myeloma and non-Hodgkin's lymphoma, when taken alone or in combination with traditional anticancer drugs [3][4][5][6][7]. Similarly, preliminary studies indicated that proteasome inhibitors induce clinical responses in patients with acute leukemia, prostate cancer, renal cell carcinoma, neuroendocrine tumors, and in children solid tumors [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Heavy patients' pretreatment and/or pre-existing diseaserelated immunodepression hamper the evaluation of the immune effects of proteasome inhibitors in humans. However, lymphopenia was reported in some of the clinical studies carried out to date [4, 6,7] and may be related to inhibition of intracellular signaling pathways and/or to a direct pro-apoptotic effect of bortezomib in normal and malignant lymphocytes [17, 20, 22, 26, and A.N., unpublished observations]. On the other hand, proteasome inhibitors were shown to delay neutrophil apoptosis by favoring accumulation of the anti-apoptotic factor Mcl-1 [17,27].…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

et al. 2006

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Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen‐presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte‐derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up‐regulation and intracellular redistribution of Bcl‐2‐associated X protein (Bax), a pro‐apoptotic Bcl‐2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen‐presenting cell level.

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“…3,4 Single-agent bortezomib demonstrated clinical activity in several other hematologic malignancies 5 with especially encouraging results in relapsed or refractory mantle cell lymphoma (MCL). [6][7][8] Objective response is achieved in 29-45% of MCL patients; however, complete remission rates are low and median duration of response short. These limitations may be overcome by combining bortezomib with conventional chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma

Weigert

Pastore

Rieken³

et al. 2007

Leukemia

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Single-agent bortezomib, a potent, selective and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the patients; however, complete remission rates are low and duration of response proved to be short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Here we present two case reports and in vitro data suggesting synergistic efficacy of bortezomib combined with cytarabine in MCL. Interestingly, efficacy in vitro correlated with sequence of treatment, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach.

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Phase II Clinical Experience With the Novel Proteasome Inhibitor Bortezomib in Patients With Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma

Abstract: These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.

Cited by 530 publications

References 29 publications

Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells

Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma

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