Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers

Abstract

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.

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

“…Similarly, in the case of myeloma, NFV was able to enhance bortezomib to overcome both bortezomib and carfilzomib resistance, again, attributed to ER stress leading to increased unfolded protein response (UPR) pathway-induced apoptosis 46. Additionally, owing to its influence on cellular stress, NFV has also been considered in combination with radiation therapy 33,39,47,48. To consider NFV’s application in the treatment of pediatric leukemia, we examined a panel of mechanistically diverse chemotherapeutic drugs in combination with NFV.…”

HIV‐1, HAART and cancer: A complex relationship

“…PIs induce cell growth arrest, endoplasmic reticulum stress, caspase‐dependent apoptosis, autophagy (for review see). Moreover, PIs are known for their antiangiogenic and radiosensitizing effects . PIs action is associated with inhibition of phosphatidylinositol 3‐kinase (PI3K)/Akt pathway; one of the possible mechanisms is binding to Hsp90 and inhibiting its chaperone function followed by decreased PI3K/Akt signaling .…”

“…Together and independently of each other, PI3K and its downstream kinase Akt regulate various cell processes such as growth, proliferation, survival, migration, apoptosis and their hyperactivation is a cancer hallmark . PI3K/Akt signaling in cancer inhibits apoptotic enzymes; promotes activation of mTOR and NF‐κB axes that regulate transcription, increase cell growth, survival, proliferation, increase matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) expression, associated with migration and angiogenesis, respectively; causes chemo/radiotherapy resistance by misregulation of DNA damage response . Akt, VEGF, MMPs and other important cancer‐phenotype proteins are partners of Hsp90, the latter works as a molecular chaperone and guarantees correct folding of its substrates .…”

“…Moreover, PIs are known for their antiangiogenic and radiosensitizing effects. 141,143 PIs action is associated with inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt pathway; one of the possible mechanisms is binding to Hsp90 and inhibiting its chaperone function followed by decreased PI3K/Akt signaling. 137,138 Together and independently of each other, PI3K and its downstream kinase Akt regulate various cell processes such as growth, proliferation, survival, migration, apoptosis and their hyperactivation is a cancer hallmark.…”

“…144,145 PI3K/Akt signaling in cancer inhibits apoptotic enzymes; promotes activation of mTOR and NF-κB axes that regulate transcription, increase cell growth, survival, proliferation, increase matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) expression, associated with migration and angiogenesis, respectively; causes chemo/radiotherapy resistance by misregulation of DNA damage response. 143,[146][147][148][149] Akt, VEGF, MMPs and other important cancer-phenotype proteins are partners of Hsp90, the latter works as a molecular chaperone and guarantees correct folding of its substrates. 150 Hsp90 † Both indinavir and nelfinavir are no longer recommended accordingly to the latest guidelines of HIV treatement.…”