Diminished Sensitivity of Chronic Lymphocytic Leukemia Cells to ABT-737 and ABT-263 Due to Albumin Binding in Blood

Vogler, Meike; Furdas, Silviya D.; Jung, Manfred; Kuwana, Tomomi; Dyer, Martin J. S.; Cohen, Gerald M.

doi:10.1158/1078-0432.ccr-10-0777

Cited by 46 publications

(35 citation statements)

References 27 publications

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“…27,28 Both ABT-263 and ABT-199 induced a rapid concentration-dependent apoptosis in primary CLL cells, which was evident both at early times (4 h) and at low nanomolar concentrations in agreement with previous studies. 10,29 The only other inhibitor to induce a similar rapid concentration-dependent induction of apoptosis in primary CLL cells was UCB-1350883, although it was much less potent than either ABT-263 or ABT-199 (Figure 4b). None of the other inhibitors tested (BI97C1, BI112D1 and TW-37) exhibited rapid apoptosis even at high concentrations (30 mM; Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-X L but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak-and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2-or BCL-X L -dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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“…We have previously shown that the presence of albumin decreases the efficacy of both compounds to induce apoptosis of CLL cells and that ABT-263 has a higher affinity for albumin and is therefore more efficiently sequestered by this plasma protein. 31 To investigate whether the binding of drug to albumin was responsible for the loss of sensitivity in whole blood, we incubated washed platelets in HBS containing 3% human serum albumin. The addition of albumin resulted in a loss of sensitivity to ABT-737 and ABT-263, confirming that albumin sequesters both drugs.…”

Section: Platelets Are More Sensitive To Abt-263 Than To Abt-737mentioning

confidence: 99%

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

Vogler

Hamali

Sun

et al. 2011

Blood

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162

147

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Apoptosis in megakaryocytes results in the formation of platelets. The role of apoptotic pathways in platelet turnover and in the apoptotic-like changes seen after platelet activation is poorly understood. ABT-263 (Navitoclax), a specific inhibitor of antiapoptotic BCL2 proteins, which is currently being evaluated in clinical trials for the treatment of leukemia and other malignancies, induces a doselimiting thrombocytopenia. In this study, the relationship between BCL2/BCL-X L inhibition, apoptosis, and platelet activa- IntroductionAll nucleated cells in multicellular organisms are genetically programmed to undergo apoptosis to remove unnecessary or damaged cells from the whole organism. This program has been recognized as the central mechanism of platelet production from megakaryocytes. 1 However, the role of apoptosis in anuclear, mature platelets is less well characterized, with apoptotic-like changes seen in both aging platelets and in the formation of procoagulant microparticles after agonist stimulation.Two main pathways lead to the execution of apoptosis: the extrinsic and the intrinsic (or mitochondrial) pathways. Both converge into the activation of caspases, which are proteases that cleave Ͼ 500 cellular targets and induce typical morphologic changes associated with apoptosis in nucleated cells. A critical step in the intrinsic pathway is the loss of mitochondrial membrane potential (MMP) and the release of cytochrome c into cytosol, where it triggers the activation of caspase-9. Therefore, the release of cytochrome c from mitochondria needs to be tightly regulated: a function that is fulfilled by the BCL2 protein family, which consists of proapoptotic and antiapoptotic members that promote or block the release of cytochrome c, respectively. 2,3 The proapoptotic family members BAX and BAK play an essential role in directly mediating the release of cytochrome c by forming a pore in the outer mitochondrial membrane. Antiapoptotic BCL2 proteins, including BCL2, BCL-X L , BCL-w, MCL1, and BCL2A1, prevent the activation of BAX and BAK. Besides their function in regulating mitochondrial cytochrome c release, BCL2 proteins have also been implicated in the regulation of intracellular calcium homeostasis at the endoplasmic reticulum (ER), possibly by interacting with inositol triphosphate receptors. 4,5 Because of their key role, the antiapoptotic BCL2 proteins are attractive targets for anticancer therapy, with several small molecule inhibitors currently in preclinical testing or early clinical trials. 6,7 Among these, the most promising and specific inhibitors are ABT-263 (Navitoclax) and 9 ABT-737 shows promising antitumor activity in animal models of leukemia and lymphoma. A related compound, ABT-263, is metabolically more stable and currently in phase 1 and 2 clinical trials for leukemia and other malignancies. 10 Both compounds have often been regarded as interchangeable because they bind with high affinity to BCL2, BCL-X L , and BCL-w but do not inhibit MCL1 or BCL2A1. 11 Early results from the clinica...

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“…This binding prevents the sequestration of pro-apoptotic proteins, resulting in the induction of cell death. In vitro, ABT-263 has been shown to rapidly induce apoptosis in various cell lines (112) as well as primary CLL cells (113). In a phase I clinical study, this compound was reported to be safe and active in patients with relapsed CLL (114).…”

Section: Therapeutic Strategies To Disrupt the Dialog Between Cll Celmentioning

confidence: 99%

Structure and function of the hematopoietic cancer niche focus on chronic lymphocytic leukemia

Kipps¹

2012

Front Biosci

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Chronic Lymphocytic Leukemia (CLL) is a B cell malignancy characterized by the accumulation of mature monoclonal CD5-positive B cells in the blood, secondary lymphoid tissues, and marrow. The infiltration of CLL cells in lymphoid tissues is a key element of disease pathogenesis. It is in such tissues that are found the microenvironments that provide CLL cells protection from spontaneous and/or drug-induced apoptosis. CLL cells actively shape their microenvironment by producing cytokines and chemokines, and by subverting normal accessory cells to promote leukemia-cell survival, proliferation, and escape from immune detection. In this review, we discuss how CLL cells disrupt the niches required for normal hematopoiesis or immune function and subvert normal cells in the microenvironment to support neoplastic cell growth and survival.

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Diminished Sensitivity of Chronic Lymphocytic Leukemia Cells to ABT-737 and ABT-263 Due to Albumin Binding in Blood

Cited by 46 publications

References 27 publications

Evaluation and critical assessment of putative MCL-1 inhibitors

Evaluation and critical assessment of putative MCL-1 inhibitors

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation

Structure and function of the hematopoietic cancer niche focus on chronic lymphocytic leukemia

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