The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies

Paoluzzi, Luca; Gönen, Mithat; Bhagat, Govind; Furman, Richard R.; Gardner, Jeffrey R.; Scotto, Luigi; Gueorguiev, Volodia D.; Heaney, Mark L.; Manova, Katia; O’Connor, Owen A.

doi:10.1182/blood-2007-12-130781

Cited by 111 publications

(89 citation statements)

References 47 publications

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“…Taken together, these data suggest that the clinical testing of compounds of the same class as ABT-737 is desirable in this setting where there is an urgent and unmet need for improved therapies. A major difference between our cohort and those reported earlier 23,26,27,45 is the significant number of samples that are less sensitive to ABT-737 as a single agent (Figure 1a). It is well recognized that multiple factors, both intrinsic and extrinsic (for example cytokines, use of stromal co-culture to resemble the in vivo microenvironment), influence responsiveness of CLL cells in culture.…”

Section: Discussioncontrasting

confidence: 47%

“…The finding that the majority of primary CLL samples are sensitive to ABT-737 is consistent with earlier reports. 23,26,27,45 However, we have shown that there is a significant variability (over 100-fold) in sensitivity among CLL samples, and that in particular, there are some patients with disease that is moderately resistant to this class of agent. Within that group, two patterns of dose-responsiveness were observed (Figure 1b, 3rd and 4th panels).…”

Section: Resultsmentioning

confidence: 99%

“…Like the other CLL cohorts that have been studied, 23,26,27,45 most of the clinical samples studied here proved sensitive to ABT-737 in vitro (Figure 1a). Of particular interest, we found that of six patients who were chemo-refractory, samples from five responded robustly to ABT-737 as a single agent (Table 1).…”

Section: Discussionmentioning

confidence: 99%

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The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia

et al. 2009

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As chronic lymphocytic leukemia (CLL) is characterized by overexpression of pro-survival BCL2, compounds that mimic its physiological antagonists, the BH3-only proteins, may have a role in treatment of this disease. ABT-737 is a BH3 mimetic compound that selectively targets BCL2 and BCLX L . In the present work, we report that ABT-737 is highly effective (LC 50 o50 nM) as a single agent against most (21/30) primary CLL samples, but that a sizable minority is relatively insensitive. In vitro sensitivity to ABT-737 could not be simply predicted by the patients' clinical features, including response to prior therapy or known prognostic markers (CD38 expression, 17p deletion), or the relative expression of BCL2 family proteins (BCL2, MCL1, BAX, BIM). Strikingly, co-incubation with cytotoxic agents (dexamethasone, etoposide, fludarabine, doxorubicin) sensitized most CLL samples to ABT-737, but this could not be predicted by responses to either ABT-737 or the cytotoxic agent alone. Of 17 samples least sensitive to ABT-737, 13 were sensitized by co-treatment with at least one cytotoxic agent. These data indicate that combination of ABT-737 with a second anti-leukemic agent would improve response rates and suggest a potential role for combination therapies that include BH3 mimetics for the treatment of this disease.

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Section: Discussioncontrasting

confidence: 47%

Section: Resultsmentioning

confidence: 99%

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The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia

et al. 2009

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“…Bcl-2 inhibitors also sensitize various lymphoid malignancies to proteasome inhibitors. 101 Resistance to fludarabine may also be mediated by other Bcl-2 family members such as increased expression of Mcl-1, which is associated with a poor prognosis. 102,103 Development of specific Mcl-1 inhibitors is in progress based on the crystal structure of Mcl-1.…”

Section: Targeting Translation Governed By Pi3k Pathway Am Martelli Ementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…Synergistic activation of the Noxa/Mcl-1 and Bad/Bcl-xL pathways is mimicked by using the relatively unspecific BH3-mimetic obatoclax (GX15-070) targeting both pathways at the same time [42]. However, enhanced apoptosis was also observed, when the Bad-mimetic ABT-737 was combined with bortezomib, homoharringtonine, N-(4-hydroxy-phenyl)retinamid, Sorafenib, Carboplatin, or TRAIL [43][44][45][46][47][48]. Since ABT-737 targets only Bcl-2, Bcl-xL, and Bcl-w, the former mentioned drugs probably activate the Noxa/Mcl-1 pathway.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis

Rudner

Elsaesser

Müller

et al. 2010

Biochemical Pharmacology

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Please cite this article as: Rudner J, Elsaesser SJ, Müller A-C, Belka C, Jendrossek V, Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies

Cited by 111 publications

References 47 publications

The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia

The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis

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