ABT-737 Synergizes with Bortezomib to Induce Apoptosis, Mediated by Bid Cleavage, Bax Activation, and Mitochondrial Dysfunction in an Akt-Dependent Context in Malignant Human Glioma Cell Lines

Abstract

We observed that glioma cells are differentially sensitive to

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

“…Our results showed that the Combined treatment with dinaciclib and ABT-737 induced the loss of mitochondrial membrane potential, activated the mitochondrial pathway of apoptosis in glioma, as evidenced by cleavage of caspase-3 and PARP (caspase-9, data not shown) and accumulation of cytosolic cytochrome c, smac/DIABLO, apoptosis-inducing factor, and activation of Bax. The activation of Bax, including Bax conformational changes and oligomerization, appears to play a crucial role in the initiation of dinaciclib-and ABT-737-induced apoptosis, consistent with our observation that the activation of Bax, including Bax conformational changes and oligomerization, appears to play an important role in the initiation of apoptosis after targeted therapies in gliomas (Premkumar et al, 2012;Foster et al, 2014). Annis et al (2005) presented evidence that Bax inserts into the mitochondrial outer membrane as a monomer and then undergoes a conformational change and homooligomerization to form pores.…”

“…have demonstrated that malignant human glioma cells are resistant to ABT-737, with an IC50 around 30-50 mM after 24 hours of exposure (Premkumar et al, 2012). Interestingly, as shown in Fig.…”

“…In Vitro Cross-Linking and Analysis of Bax Oligomerization. Cytosolic and membrane fractions were prepared by selective plasma membrane permeabilization with 0.05% digitonin, followed by membrane solubilization with 1% CHAPS as described elsewhere (Premkumar et al, 2012). Briefly, control and experimental cells in dishes were treated with 0.05% digitonin in isotonic buffer (10 mM HEPES, 150 mM NaCl, 1.5 mM MgCl 2 , 1 mM EGTA, pH 7.4) containing protease inhibitors [1 mM 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride, 0.8 mM aprotinin, 50 mM bestatin, 15 mM E-64, 20 mM leupeptin, 10 mM pepstatin A], for 1 or 2 minutes at room temperature.…”

“…In preclinical experiments, ABT-737 showed strong antiproliferative and proapoptotic effects in a wide variety of cell types (Bodet et al, 2011). Many cancers, particularly gliomas, are resistant to apoptosis by upregulation of antiapoptotic Bcl-2 family members (Premkumar et al, 2012). One shortcoming with its use is that Mcl-1, a member of the Bcl-2 family, is poorly inhibited by ABT-737 and thus is a major cause of resistance.…”

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

“…As a single agent ABT-737, a novel Bcl -2/ Bcl -xL inhibitor triggers apoptosis in various types of human cancers including multiple myeloma, leukemia, lymphoma and small cell lung cancer. [25][26][27][28][29] However, we [30][31][32] and others 33 have demonstrated that ABT-737 minimally inhibits cell growth in glioma when used as a single agent. The complexity of the interactions between cell surface receptors and downstream signaling targets has called into question the clinical utility of blocking any target in isolation, and the results of single agent-based strategies have to date been disappointing in patients with glioma.…”