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

Purpose To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent and mantle-cell lymphoma (MCL). Patients and Methods Patients with indolent and MCL were eligible. Bortezomib was given at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11. Patients were required to have received no more than three prior chemotherapy regimens, with at least 1 month since the prior treatment, 3 months from prior rituximab, and 7 days from prior corticosteroids; absolute neutrophil count more than 1,500/μL (500/μL if documented bone marrow involvement); and platelet count more than 50,000/μL. Results Twenty-six patients were registered, of whom 24 were assessable. Ten patients had follicular lymphoma, 11 had MCL, three had small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), and two had marginal zone lymphoma. The overall response rate was 58%, with one complete remission (CR), one unconfirmed CR (CRu), and four partial remissions (PR) among patients with follicular non-Hodgkin's lymphoma (NHL). All responses were durable, lasting from 3 to 24+ months. One patient with MCL achieved a CRu, four achieved a PR, and four had stable disease. One patient with MCL maintained his remission for 19 months. Both patients with marginal zone lymphoma achieved PR lasting 8+ and 11+ months, respectively. Patients with SLL or CLL have yet to respond. Overall, the drug was well tolerated, with only one grade 4 toxicity (hyponatremia). The most common grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7). Conclusion These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.

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The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status

Blood ◽

10.1182/blood-2005-05-2091 ◽

2006 ◽

Vol 107 (1) ◽

pp. 257-264 ◽

Cited By ~ 329

Author(s):

Patricia Pérez-Galán ◽

Gaël Roué ◽

Neus Villamor ◽

Emili Montserrat ◽

Elias Campo ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Conformational Changes ◽

Proteasome Inhibitor ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Ros Generation ◽

Mitochondrial Depolarization ◽

Mantle Cell ◽

P53 Status

Abstract Mantle-cell lymphoma (MCL) is a mature B-cell lymphoma with an aggressive course and generally poor prognosis. Conventional chemotherapy has little efficacy. Bortezomib is a novel, reversible, and highly specific proteasome inhibitor that appears as a new hope for MCL treatment. We have analyzed the in vitro sensitivity to bortezomib in 4 MCL cell lines and in primary tumor cells from 10 MCL patients. Bortezomib induced phosphatidylserine exposure, mitochondrial depolarization, ROS generation, Bax and Bak conformational changes, and caspase activation. In addition, ROS scavengers, but not pancaspase inhibitors, blocked all apoptosis hallmarks. Protein and mRNA-expression analysis, revealed marked up-regulation of the BH3-only protein Noxa, between 4 to 6 hours after bortezomib addition, independent of p53 status. However, this up-regulation was faster and higher in cells with functional p53. Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing to this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells. Noxa interacts with the antiapoptotic protein Mcl-1 and promotes Bak release from Mcl-1, suggesting that up-regulation of Noxa might counteract Mcl-1 accumulation after bortezomib treatment. These findings should be useful to extend the therapeutic strategies in MCL patients and to improve their prognosis.

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The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78

Blood ◽

10.1182/blood-2010-04-278853 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1270-1279 ◽

Cited By ~ 73

Author(s):

Gaël Roué ◽

Patricia Pérez-Galán ◽

Ana Mozos ◽

Mónica López-Guerra ◽

Sílvia Xargay-Torrent ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Unfolded Protein Response ◽

Proteasome Inhibitor ◽

Cell Lymphoma ◽

Apoptotic Cell ◽

Hsp90 Inhibitor ◽

Unfolded Protein ◽

Mantle Cell ◽

Protein Response

Abstract Despite the promising introduction of the proteasome inhibitor bortezomib in the treatment of mantle cell lymphoma (MCL), not all patients respond, and resistance often appears after initial treatment. By analyzing a set of 18 MCL samples, including cell lines with constitutive or induced resistance to bortezomib, we found a high correlation between loss of sensitivity to the proteasome inhibitor and up-regulation of the prosurvival chaperone BiP/Grp78. BiP/Grp78 stabilization was ensured at a posttranscriptional level by an increase in the chaperoning activity of heat shock protein of 90 kDa (Hsp90). In bortezomib-resistant cells, both BiP/Grp78 knockdown and cell pretreatment with the Hsp90 inhibitor of the ansamycin class, IPI-504, led to synergistic induction of apoptotic cell death when combined with bortezomib. Cell exposure to the IPI-504–bortezomib combination provoked the dissociation of Hsp90/BiP complexes, leading to BiP/Grp78 depletion, inhibition of unfolded protein response, and promotion of NOXA-mediated mitochondrial depolarization. The IPI-504–bortezomib combination also prevented BiP/Grp78 accumulation, thereby promoting apoptosis and inhibiting the growth of bortezomib-resistant tumors in a mouse model of MCL xenotransplantation. These results suggest that targeting unfolded protein response activation by the inhibition of Hsp90 may be an attractive model for the design of a new bortezomib-based combination therapy for MCL.

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