Proteasome inhibitIon specifically sensitizes leukemic cells to anthracyclin-induced apoptosis through the accumulation of Bim and Bax pro-apoptotic proteins

Pigneux, Arnaud; Fx, Mahon; Moreau‐Gaudry, François; Uhalde, Maïalen; H, de Verneuil; Lacombe, Francis; Reiffers, J.; Milpied, Noël; Praloran,; Belloc, Françis

doi:10.4161/cbt.6.4.4226

Cited by 31 publications

(18 citation statements)

References 32 publications

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“…The results of the present study indicated that Bim may be important in bortezomib+daunorubicin-induced cell death. Consistent with this, several reports have shown that Bim-targeting contributes to the bortezomib-based combination regime (33–35). However, whether Bim contributed to bortezomib+daunorubicin-induced mitochondria impairment, and how cotreatment with bortezomib and daunorubicin upregulated the expression of Bim required further investigation.…”

Section: Discussionsupporting

confidence: 70%

Combination of bortezomib and daunorubicin in the induction of apoptosis in T-cell acute lymphoblastic leukemia

Jia

et al. 2017

Molecular Medicine Reports

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Despite advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), the outcome of T-ALL treatment remains unsatisfactory, therefore, more effective treatment is urgently required. The present study examined the cytotoxicities of bortezomib in combination with daunorubicin against human Jurkat and Molt-4 T-ALL cells and primary T-ALL cells. Compared with treatment alone, co-exposure of cells to bortezomib and daunorubicin resulted in a significant increase in cell death in the Jurkat cells, as evidenced by the increased percentage of Annexin V-positive cells, the formation of apoptotic bodies. In addition, the administration sequence of bortezomib and daunorubicin had an effect on cell viability. Treatment with bortezomib followed by daunorubicin treatment was more effective, compared with treatment with daunorubicin followed by bortezomib. Co-treatment with bortezomib and daunorubicin markedly enhanced the activation of caspase-3, -8 and -9, which was reversed by the pan-caspase inhibitor, Z-VAD-FMK. In addition, cotreatment with bortezomib and daunorubicin enhanced the collapse of mitochondrial transmembrane potential and upregulated the proapoptotic protein, B-cell lymphoma 2 (Bcl-2)-interacting mediator of cell death (Bim), but not Bcl-2 or Bcl-extra large. Consistent with this, it was demonstrated that cotreatment of bortezomib and daunorubicin efficiently induced apoptosis in primary T-ALL cells, and cell death was associated with the collapse of mitochondrial transmembrane potential and the upregulation of Bim. Taken together, these findings indicated that the combination of bortezomib and daunorubicin significantly enhanced their apoptosis-inducing effect in T-ALL cells, which may warrant further investigation in preclinical and clinical investigations.

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Section: Discussionsupporting

confidence: 70%

Combination of bortezomib and daunorubicin in the induction of apoptosis in T-cell acute lymphoblastic leukemia

Jia

et al. 2017

Molecular Medicine Reports

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“…Acute myeloid leukaemia cells express higher levels of proteasomes compared with normal peripheral blood cells and are more sensitive to proteasome inhibition compared with normal haematopoietic cells [70,72,73]. Phase I trials have examined bortezomib monotherapy for paediatric acute leukaemia [74].…”

Section: Bortezomib In Leukaemiamentioning

confidence: 99%

The therapeutic potential of the proteasome in leukaemia

McCloskey

McMullin²,

Walker

et al. 2008

Hematological Oncology

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Many cellular processes converge on the proteasome, and its key regulatory role is increasingly being recognized. Proteasome inhibition allows the manipulation of many cellular pathways including apoptotic and cell cycle mechanisms. The proteasome inhibitor bortezomib has enhanced responses in newly diagnosed patients with myeloma and provides a new line of therapy in relapsed and refractory patients. Malignant cells are more sensitive to proteasome inhibition than normal haematopoietic cells. Proteasome inhibition enhances many conventional therapies and its role in leukaemia is promising.

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“…The antitumor effect against leukemic cells of a combination of proteasome inhibitors with other drugs such as anthracyclin [34], arsenic trioxide [35] and more recently TRAIL itself has already been described by different authors. Particularly, Riccioni et al [27] showed that M4 and M5 AML display a high sensitivity to bortezomib-mediated apoptosis and this effect is increased when TRAIL is added.…”

Section: Discussionmentioning

confidence: 99%

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

Conticello

Adamo²,

Vicari³

et al. 2008

Acta Haematol

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Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60–70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 µM for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy.

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Proteasome inhibitIon specifically sensitizes leukemic cells to anthracyclin-induced apoptosis through the accumulation of Bim and Bax pro-apoptotic proteins

Cited by 31 publications

References 32 publications

Combination of bortezomib and daunorubicin in the induction of apoptosis in T-cell acute lymphoblastic leukemia

Combination of bortezomib and daunorubicin in the induction of apoptosis in T-cell acute lymphoblastic leukemia

The therapeutic potential of the proteasome in leukaemia

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

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