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

Daniel R Premkumar, etc
JPET, 2012

We observed that glioma cells are differentially sensitive to ABT-737, and that 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 BH3 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 NF-¿B, was found to enhance sensitivity of ABT-737 in PTEN-wild type, but not PTEN-mutated glioma cell lines. We therefore investigated the association between PI3Kinase/Akt activation and resistance to the combination of ABT-737 and bortezomib in PTEN deficient glioma cells. Genetic and pharmacological inhibition of PI3 kinase 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 PI3-kinase/Akt-dependent protection may occur upstream of the mitochondria. This study demonstrates that interference with multiple apoptosis-resistance signaling nodes, including NF-¿B, Akt, and Bcl2, may be required to induce apoptosis in highly resistance glioma cells, and that therapeutic strategies that target the PI3-kinase/Akt pathway may be have a selective role for cancers lacking PTEN function.

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doi: 10.1124/jpet.112.191536
University of Pittsburgh