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

• Published in: The Journal of pharmacology and experimental therapeutics 2012-06, Vol.341 (3), p.859-872
• Main Authors: Premkumar, Daniel R, Jane, Esther P, DiDomenico, Joseph D, Vukmer, Natalie A, Agostino, Naomi R, Pollack, Ian F
• Format: Article
• Language: English
• Subjects: Annexins - metabolism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; BH3 Interacting Domain Death Agonist Protein - metabolism; Biphenyl Compounds - pharmacology; Blotting, Western; Boronic Acids - pharmacology; Bortezomib; Cell Line, Tumor - metabolism; Cell Proliferation; Cellular and Molecular; Drug Synergism; Glioma - metabolism; Glioma - pathology; Humans; Mitochondrial Diseases - metabolism; NF-kappa B - metabolism; Nitrophenols - pharmacology; Piperazines - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Pyrazines - pharmacology; Sulfonamides - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.112.191536

We observed that glioma cells are differentially sensitive to N-{4-[4-(4'-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide (ABT-737) and administration of ABT-737 at clinically achievable doses failed to induce apoptosis. Although elevated Bcl-2 levels directly correlated with sensitivity to ABT-737, overexpression of Bcl-2 did not influence sensitivity to ABT-737. To understand the molecular basis for variable and relatively modest sensitivity to the Bcl-2 homology domain 3 mimetic drug ABT-737, the abundance of Bcl-2 family members was assayed in a panel of glioma cell lines. Bcl-2 family member proteins, Bcl-xL, Bcl-w, Mcl-1, Bax, Bak, Bid, and Noxa, were found to be expressed ubiquitously at similar levels in all cell lines tested. We then examined the contribution of other apoptosis-resistance pathways to ABT-737 resistance. Bortezomib, an inhibitor of nuclear factor-kappaB (NF-κB), was found to enhance sensitivity of ABT-737 in phosphatase and tensin homolog on chromosome 10 (PTEN)-wild type, but not PTEN-mutated glioma cell lines. We therefore investigated the association between phosphatidylinositol 3-kinase (PI3K)/Akt activation and resistance to the combination of ABT-737 and bortezomib in PTEN-deficient glioma cells. Genetic and pharmacological inhibition of PI3K inhibition sensitized PTEN-deficient glioma cells to bortezomib- and ABT-737-induced apoptosis by increasing cleavage of Bid protein, activation and oligomerization of Bax, and loss of mitochondrial membrane potential. Our data further suggested that PI3K/Akt-dependent protection may occur upstream of the mitochondria. This study demonstrates that interference with multiple apoptosis-resistance signaling nodes, including NF-κB, Akt, and Bcl-2, may be required to induce apoptosis in highly resistant glioma cells, and therapeutic strategies that target the PI3K/Akt pathway may have a selective role for cancers lacking PTEN function.