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 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.

• Authors: Daniel R Premkumar, Esther P Jane, Joseph D DiDomenico, Natalie A Vukmer, Naomi R Agostino, Ian F Pollack
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 341 Issue 3 Pg. 859-72 (Jun 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22393246 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Annexins
• Antineoplastic Agents
• BH3 Interacting Domain Death Agonist Protein
• BID protein, human
• Biphenyl Compounds
• Boronic Acids
• NF-kappa B
• Nitrophenols
• Piperazines
• Pyrazines
• Sulfonamides
• bcl-2-Associated X Protein
• Bortezomib
• Proto-Oncogene Proteins c-akt

Topics

• Annexins (metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• BH3 Interacting Domain Death Agonist Protein (metabolism)
• Biphenyl Compounds (pharmacology)
• Blotting, Western
• Boronic Acids (pharmacology)
• Bortezomib
• Cell Line, Tumor (metabolism)
• Cell Proliferation
• Drug Synergism
• Glioma (metabolism, pathology)
• Humans
• Mitochondrial Diseases (metabolism)
• NF-kappa B (metabolism)
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrazines (pharmacology)
• Sulfonamides (pharmacology)
• bcl-2-Associated X Protein (metabolism)