Cellular resistance in tumour
cells to different
therapeutic approaches has been a limiting factor in the curative
treatment of
cancer. Resistance to
therapeutic radiation is a common phenomenon which significantly reduces
treatment options and impacts
survival. One of the mechanisms of acquiring resistance to
ionizing radiation is the overexpression or activation of various
oncogenes like the EGFR (
epidermal growth factor receptor),
RAS (
rat sarcoma)
oncogene or loss of PTEN (
phosphatase and
tensin homologue) which in turn activates the
phosphatidyl inositol 3-
kinase/
protein kinase B (PI3-K)/AKT pathway responsible for
radiation resistance in various tumours. Blocking the pathway enhances the
radiation response both
in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour
cells and not in the normal host
cells), it is an excellent candidate target for
molecular targeted therapy to enhance
radiation sensitivity. In this regard,
HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour
cells, have been shown to sensitize various tumour
cells to
radiation both
in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic
drugs. This
review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the
role of
HIV protease inhibitors especially
nelfinavir as a potential candidate
drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different
malignancies.