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

J Pharmacol Exp Ther. 2012 Jun;341(3):859-72. doi: 10.1124/jpet.112.191536. Epub 2012 Mar 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Glioma / 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*

Substances

  • 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