PDK-1/Akt pathway as targets for chemosensitizing effects

by 1975- Tseng, Ping-Hui

Cancer is the leading causes of human deaths all over the world. The growing understanding in cancer biology provides the researchers to develop molecularly targeted therapeutic strategies. However, the toxicity and resistance limit the applications for molecularly targeted agents. Here, we proposed that inhibiting PI3K/PDK-1/Akt signaling pathway, which is critical in controlling cell survival and proliferation, is able to enhance the therapeutic effects and overcome resistance of the current used molecularly targeted drugs. Imatinib (STI571; Gleevec), a selective bcr-abl tyrosine kinase inhibitor, is approved to treat patients with chronic myelogenous leukemia (CML). However, patients in more advanced phases of CML frequently develop resistance to the treatment. Mutations within the kinase domain for the binding of imatininb attributes as one of the major imatinib-resistant mechanisms. The effects of imatinib each alone and in combination with OSU-03012, a novel celecoxib-derived PDK-1 inhibitor, was evaluated in a panel of Bcr-Abl positive Ba/F3 cell lines without or with mutations. The IC50 values for OSU- 03012 alone were comparable, while the sensitivities to imatinib alone were differed. The combination treatment, however, caused a synergistic enhancement of apoptosis in these cells, including those that are resistant to imatinib. ii HER2/neu is frequently over-expressed in breast cancers that are characterized by aggressive tumor progression and resistant to current therapies. The effects of trastuzumab (Herceptin), a monoclonal antibody targeting to HER2/neu, alone and in combination with OSU-03012 were evaluated in a panel of breast cancer cell lines. The IC50 values for OSU-03012 alone in four cell lines were comparable, while the sensitivities to trastuzumab alone were mainly dependent on the HER2/neu expression level or resistant phenotypes. The combination treatments, however, caused a synergistic enhancement of anti-proliferation in HER2/neu positive cell lines, including SKBR3/IGF-IR, as a resistant phenotype, that responded poorly to trastuzumab. These results demonstrate the potential clinical value of a therapeutic strategy to sensitize cancer cells to molecularly targeted drugs by co-targeting PDK-1/Akt signaling. More importantly, the co-treatments are able to overcome drug resistance. iii