Lung cancer is one of the most common causes of
cancer death worldwide. Although recent advances in
chemotherapy and
radiation therapy have yielded modest improvements in patient outcomes, overall survival remains poor. Therefore, new therapeutic targets are needed.
Phosphoinositide-dependent kinase-1 (PDK1) is one potential target. The aim of the present studies was to investigate the potential of a
celecoxib-derived PDK1 inhibitor (
OSU03013), that does not inhibit
cyclooxygenase-2, to kill
lung cancer cells in vitro. Using human
non-small-cell lung cancer A549 cells,
OSU03013 dose-dependently induced apoptosis. After 6 h of treatment with 7.5 microM
OSU03013, 26% of the cells were apoptotic, compared to 4% of the control cells as determined by measuring the sub-G1 peak of
propidium iodide stained cells with flow cytometry. A similar increase in apoptosis was evident using the Cell Death ELISA assay. OSU03013-induced apoptosis was accompanied by a reduction in the mitochondrial membrane potential, the release of
cytochrome c and the cleavage of
caspase-3. Surprisingly, the phosphorylation of Akt at
serine 473 was increased in A549 cells treated with 7.5 microM
OSU03013. However, the toxicity of
OSU03013 was reduced in A549 cells expressing a constitutively active form of Akt. These data demonstrate that
OSU03013 induces apoptosis in A549 cells via the mitochondrial pathway. Inhibition of the Akt pathway appears uninvolved in this toxicity, although Akt can provide protection. These results also suggest the potential of
celecoxib-derived agents to treat some forms of
lung cancer.