PDK-1/Akt pathway as targets for chemosensitizing effects
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.
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.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:cancer trastuzumab chronic myeloid leukemia imatinib protein tyrosine kinase
Date of Publication: