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Departments of Biochemistry (A.Y., M.A.P., D.H., Y.H., C.M., A.P.P., S.G., P.D.), Medicine (H.H., S.G.), and Radiation Oncology (A.Y., P.D.), Virginia Commonwealth University, Richmond, Virginia; Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio (C.-S.C.); Department of Radiation Oncology, Wake Forest University, Winston Salem, North Carolina (C.K.); and Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas (G.P.)
We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/AKT inhibitors, or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCLXL, and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.
Received for publication March 28, 2006.
Accepted for publication April 18, 2006.
Address correspondence to: Dr. Paul Dent, Department of Biochemistry, Massey Cancer Center Virginia Commonwealth University, Richmond, VA 23298-0058. E-mail: pdent{at}hsc.vcu.edu
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