Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research
  Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login  
  Home Print this page Email this page Small font sizeDefault font sizeIncrease font size Users Online: 1309    

   Table of Contents      
Year : 2016  |  Volume : 143  |  Issue : 2  |  Page : 145-159

Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers

1 Department of Radiation Oncology; Clinical Biology Laboratory, Department of Radiation Oncology, Advance Centre for Treatment Research & Education in Cancer, Tata Memorial Center, Navi Mumbai, India
2 Clinical Pharmacology Laboratory, Advance Centre for Treatment Research & Education in Cancer, Tata Memorial Center, Navi Mumbai, India

Date of Submission20-Feb-2014
Date of Web Publication14-Apr-2016

Correspondence Address:
Jayant S Goda
Department of Radiation Oncology, Advance Centre for Treatment Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410 210, Maharashtra
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-5916.180201

Rights and Permissions

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.

Keywords: c0 linical trials - HIV protease - inhibitors - nelfinavir - radiosensitizer

How to cite this article:
Goda JS, Pachpor T, Basu T, Chopra S, Gota V. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers. Indian J Med Res 2016;143:145-59

How to cite this URL:
Goda JS, Pachpor T, Basu T, Chopra S, Gota V. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers. Indian J Med Res [serial online] 2016 [cited 2021 Sep 20];143:145-59. Available from:


Radioresistance and chemoresistance are important contributing factors towards the failure of tumour cell kill and subsequent eradication of tumours. Strategies to overcome radioresistance or enhance radiation sensitivity include classically altering the radiation fractionation wherein a higher radiation dose is given to the tumour to overcome intrinsic radioresistance (hyperfractionation) or compensate for the tumour repopulation by reducing the overall treatment time (accelerated fractionation) [1],[2],[3],[4],[5] . A second approach is to use a combination of chemotherapy with radiotherapy, in particular concurrent chemoradiotherapy [6],[7] . This approach has shown benefit in numerous solid cancers especially in head and neck and cervical carcinoma [7],[8] . A third approach to overcome radioresistance is to modulate hypoxia in the tumour cells. This approach has been particularly useful in head and neck cancers where intrinsic hypoxia is a major factor contributing to tumour cell radioresistance. Trials using hypoxic sensitizers such as nitroimidazoles and hypoxic cytotoxins have been published [9],[10],[11],[12] . Another promising approach is the use of targeted therapy concurrently with radiation, to enhance the efficacy of radiation, e.g., epidermal growth factor receptor (EGFR) inhibitors like cetuximab in head and neck cancer [13],[14] , gefitinib, erlotinib and afatinib in lung cancer [15],[16],[17],[18] , and vascular endothelial growth factor (VEGF) inhibitor, bevacizumab in colon cancer [19],[20] . The advantage of targeted therapy is that these have a reasonably high therapeutic ratio although drug specific toxicity may occur. In this respect targeting the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K/AKT) signal transduction pathway considered to be a major pathway in radiation resistance may enhance the radiosensitivity of tumours [21],[22] . The PI3-K/AKT pathway is overexpressed in a variety of tumours [Table I]. Since this pathway is constitutively overexpressed in tumour cells, sparing the normal cells makes it an excellent target for enhancing the radiosensitivity.
Table I. Expression of AKT in various cancers

Click here to view

Though the development in the field of targeted pharmacotherapy is ongoing, the process of developing novel agents that would block the PI3-K/AKT pathway and bringing these into the clinic as interventional agents is a relatively tardy process especially when starting from novel compounds not previously tested in humans. In contrast, drugs or agents which are already in clinical practice for other diseases could be used as molecular targeting agents for anti-cancer therapy and adopted in clinics after testing them in thoroughly designed clinical trials thereby avoiding any delay in the process of drug development. Currently, such off-label use of drugs is being followed with anti-retroviral [human immunodeficiency virus (HIV) protease inhibitors, HPI's] drugs that inhibit AKT phosphorylation as candidates for not only anti-cancer therapy, but also for developing these agents as radiosensitizers. These compounds have been used as anti-HIV drugs in the clinics for the past decade and their safety profile is well documented in the literature. However, their use in combination with other cytotoxic therapies like radiation therapy (RT) and chemotherapy (CT) is under intense investigation.

The aim of the review was to collect available in vitro/in vivo data and data from clinical trials related to HIV protease inhibitors as radiosensitizers, and evaluate the role of HPI's, particularly nelfinavir, as a potential candidate drug as a radio sensitizer.

PI3-K/AKT signaling pathway and radiation resistance

Cancer cells have a tendency to acquire resistance to radio/chemotherapy [52],[53],[54] . The relevance of the PI3-K/AKT signal-transduction pathway has been shown in radioresistance [52] . One of the factors responsible for resistance to therapy is overexpression/activation of oncogenes (e.g. EGFR, RAS) and loss of tumour suppressor gene (e.g. PTEN) [55],[56],[57],[58],[59],[60],[61] . These molecular alterations ultimately lead to activation of PI3-K/AKT pathway which regulates important mechanisms of cellular radioresistance.

Akt activation and events leading to DNA damage repair: Studies have shown EGFR and RAS activation to be a major contributor to tumour radioresistance which in turn activates the PI3-K/AKT pathway thereby increasing the survival of tumour cells that have been exposed to DNA damaging agents [62],[63] . Moreover, selectively blocking this pathway reduces the tumour cell survival after irradiation [62],[63] . Cellular radioresistance is linked to the ability of the tumour cells to repair the DNA damage it incurs following exposure to DNA damaging agents. Repair can occur either by homologous recombination (HR) or non-homologous end joining (NHEJ) which is responsible for majority of the double strand DNA break repair. A major protein involved in the NHEJ repair machinery and radiotherapy response is the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [64] . The Akt has been shown to directly interact with DNA-PKcs through its C-terminal domain [65] . Akt1 and DNA-PKcs form a functional complex after radiation exposure and promotes accumulation of DNA-PKcs and stimulates DNA-PKcs kinase activity at DNA-DSB (double strand break) site for initiating DNA-DSB repair [65],[66],[67] . An alternative pathway regulating DNA-DSB repair by Akt is the upregulation of MRE11 expression after Akt activation through Akt/GSK3ß (glycogen synthase kinase-3 beta) ß-catenin/LEF-1 (lymphoid enhancer binding factor 1) pathway [68] . Another protein complex-MRE11, RAD50 and NBS1 (MRN) complex accumulates at DNA-DSB sites post radiation and acts as a sensor to recruit ATM (ataxia telangectasia mutated) which in turn is activated to phosphorylate MRN complex and a variety of other proteins involved in cell-cycle control and DNA repair [69] . Since targeting Akt leads to downregulation of MRE11 at the transcriptional level, role of Akt1 on DNA repair is ATM dependent. Fraser et al[70] have shown that the activation of MRE11-ATM-RNF168 pathway induces Akt phosphorylation thus leading to an Akt-dependent enhanced repair of DNA-DSB. AKT signalling also plays an important role in DNA repair via homologous recombination (HR) pathway. It has been shown that breast cancer patients with HR deficiency have increased phospho AKT levels and similarly tumour formation due to BRCA1 deficiency is reduced by Akt1 depletion [71] , while in BRCA1 proficient breast cancer cells HR inhibition due to AKT1 activation is a result of cytoplasmic retention of BRCA1 and RAD51 [72] . In HR-deficient cells, Akt1 signalling inhibition of HR is due to impaired Chk1 nuclear localization and subsequent disruption of Chk1-Rad51 interaction [73] . Thus, it is now clear that AKT signalling has contrasting effects on NHEJ and HR pathways. Since DNA-DSB repair is a combination of both NHEJ and HR repair pathways, AKT stimulates repair of DNA-DSB by the NHEJ through activation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) which is dominant over AKT mediated impairment of DNA-DSB repair in HR-deficient cells.

EGFR signaling by the PI3-K-AKT pathway has been shown to be involved in the regulation of DNA-PKcs and, therefore, DNA repair [64] . Likewise, evidence from in vitro studies have shown that targeting of AKT activity by small interfering RNA (siRNA) sensitizes human tumour cells to ionizing radiation [62] . Therefore, EGFR/RAS-activation either by mutation or by receptor tyrosine-kinase activity is a frequent event in human malignancy, suggesting that the PI3-K/AKT-mediated repair of DNA damage might be an important mechanism of intrinsic radioresistance [74] .

Autophagy and AKT signalling:Autophagy (or programmed cell death type II) is now considered as an important process in carcinogenesis as well as tumour cell response to radiation therapy [75],[76] . Autophagy is mainly regulated by the mammalian target of rapamycin (mTOR) pathway. Evidence suggests that PI3-K/AKT signaling plays an important role in the regulation of autophagy. Exposure of tumour cells to ionizing radiation induces autophagy. Further, inhibition of autophagy either by autophagy inhibitors [77] or genetic approaches [76] induces radiosensitization. Induction of autophagy through this pathway produces cytotoxic effect on the tumour cell. This is supported by the radiosensitizing effect of AKT inhibition and reduced cell viability in malignant glioma cells U87-MG and U87-MGΔEGFR[78] . The same group showed that AKT inhibition resulted in decreased phosphorylated p70S6 kinase, a downstream target of AKT, and induced autophagy, but not apoptosis. Also, the AKT inhibitor radiosensitized both U87-MG and U87-MGΔEGFR cells by enhancing autophagy. Further studies need to be done to identify the mechanism(s) involved in the cytoprotective effect of radiation-induced autophagy and cytotoxic effect of Akt induced autophagy on post-irradiation survival.

Tumour cell proliferation: The detrimental effect of cellular repopulation for tumour control has been extensively studied in various malignancies [79] . Tumour repopulation is affected by various factors such as cell differentiation status, cell-cycle gene regulation, and micro-environmental factors, including oxygen, neoangiogenesis and nutrient availability. A major mechanism by which cellular proliferation is enhanced in response to ionizing radiation is by induction of EGFR phosphorylation [80] . This EGFR response has been linked to several crucial components of mitogenic or proliferative signaling pathways, a major route being the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway [80] . Studies on PI3-K/AKT have mainly focused on its role in cell survival and progression [81] . Additionally, this PI3-K/AKT also amplifies tumour cell proliferation by signaling the cell cycle machinery as AKT phosphorylation prevents cyclin D1 degradation, which regulates transition of tumour cells from G1 to S phase of cell cycle resulting in radiation resistance [82],[83] .

Hypoxia and angiogenesis: Solid tumours are known to have an imbalance between oxygen delivery and oxygen consumption, resulting in hypoxia. Tumour hypoxia promotes genetic instability, thus leading the tumour towards a more malignant phenotype by stimulating the invasion of tumour cells and, therefore, metastasis [84] . Furthermore, hypoxia modulates mutations of key regulatory genes that result in overexpression of various protein products of these genes which induce resistance to treatment, resulting in an overall adverse clinical outcome [85],[86] .

PI3-K/AKT signaling has an important role in this adaptive response of tumour cells to hypoxia. As all these hypoxia-related markers are under the control of AKT, information on AKT-activation status may add significantly to the predictive potential of endogenous tumour markers. Tumour hypoxia results in increased expression of hypoxia-inducible transcription factor- 1(HIF-1), which modulates the expression of many genes involved in angiogenesis, pH regulation, and glucose metabolism which in turn drive tumour growth and progression. The protein products of these genes, such as vascular endothelial growth factor (VEGF), carbonic anhydrase-IX, the glucose transporters Glut-1 and Glut-3, osteopontin and tyrosine hydroxylase have now been recognized as potential predictive markers for clinical outcome in various tumours [87] . The interaction between hypoxia, angiogenesis and PI3-K/AKT has been shown in various malignancies [88],[89],[90],[91] and has been further corroborated by the evidence that downregulation of this signaling pathway by protease inhibitor nelfinavir resulted in decreased expression of HIF-1α and VEGF in response to radiation[92] . Another hypoxia-related product that is under the control of the PI3-K/AKT pathway is osteopontin which is increased in several tumours in response to hypoxia. Hypoxia-induced activation of AKT has been shown to activate an unknown transcriptional factor that triggers osteopontin expression [93],[94] .

Under hypoxic conditions, VEGF is one of the genes which are activated by HIF-1; while under normoxic conditions it is activated through PI3-K/AKT signalling by either upregulation of EGFR or loss of PTEN [92],[95] . VEGF expression plays an important role in neo-angiogenesis by inducing endothelial cell proliferation and vascular permeability crucial for tumour cell proliferation. Prevention of neo-angiogenesis by downregulation of VEGF either directly by the use of VEGF inhibitors such as bevacizumab or indirectly through the use of PI3K/ AKT inhibitors or EGFR inhibitors can result in a normalization of the vasculature and improved perfusion leading to a reduction of tumour cell hypoxia [96]. Two distinct pathways (one including HIF-1α translation and the other involving HIF-independent processes) have been recognized as regulators of VEGF expression, both of which involve PI3-K and AKT[92] . Morelli et al[97] observed that VEGF-A blockade, by EGFR inhibition, significantly decreased angiogenesis. A sustained control of tumour cell proliferation and angiogenesis was obtained by the combined blockade of the EGFR pathway in the tumour and the VEGF pathway in endothelial cells. These findings highlight the close relation between EGFR and VEGF inhibition and downstream signal transduction via the PI3-K/AKT pathway. This is corroborated by in vitro experiments using PI3-K inhibitor LY294002 which interrupts the PI3-K/AKT pathway resulting in decreased VEGF expression [98] .

AKT signalling and glucose metabolism leading to tumour radioresistance: Cancer cells tend to exhibit increased glucose metabolism compared to normal cells leading to excess lactate production by the process of aerobic glycolysis, also called Warburg effect [99],[100],[101] . AKT hyperactivation is believed to be associated with increased rates of glucose metabolism observed in tumour cells [102] . This may be through several mechanisms such as, regulation of GLUT-1 on plasma membrane [103] , hexokinase expression and mitochondrial protection [104] , or Akt may indirectly activate the glycolysis rate-controlling enzyme phosphofructokinase-1 (PFK1) by direct phosphorylation of phosphofructokinase-2 (PFK2) [105] , resulting in formation of fructose-2.6-bisphosphate (Fru-1,6-P2), which is a potent allosteric activator of PFK1. In vitro study on glioblastoma cell lines showed that AKT activation correlated with increased glycolysis in glioblastoma cells and tumour cell resistance [102] . Therefore, it can be postulated that the increased glycolytic rates observed by Warburg in cancer cells exhibiting mitochondrial respiration malfunction compared to normal cells may involve activation of the Akt pathway. Inhibition of glucose metabolism in cancer cells with AKT pathway inhibitors is assumed to limit glycolysis in the cancer cell and thereby the production of pyruvate and regeneration of NADPH leading to increased levels of hydrogen peroxide and hydroperoxides resulting in preferential cytotoxicity of the cancer cells via oxidative stress. Based on these assumptions, the combination of Akt pathway inhibitors with glycolytic inhibitors and/or manipulations that increase pro-oxidant production should further and preferentially cause cytotoxicity in cancer cells, with minimal to no toxicity to normal cells. Simon et al[106] using human head neck squamous cell carcinoma (HNSCC) cell lines (FaDu & cal -27) have shown that inhibition of AKT pathway disrupts glucose metabolism and induces metabolic oxidative stress in cancer cells leading to preferential cytotoxicity. These results indicate that increased Akt pathway signalling may have a significant role in the Warburg effect and this phenomenon should be exploited to selectively target cancer cells for enhancing radio- and chemo-sensitivity in cancer therapy.

Rationale for targeting the AKT pathway for radiosensitization

The P13-K/AKT pathway is a ubiquitous and evolutionary conserved pathway which triggers a cascade of downstream events that regulate various cellular functions namely, cell growth and proliferation, cell survival and motility which drives tumour progression and mediates repair of the damaged DNA resulting in radiation resistance [81],[107] . Activation of this pathway and increased intratumoral phosphorylated AKT have been linked to decreased radiation responsiveness in various malignancies [62],[89],[107] .

Clinical evidence of PI3-K/AKT pathway deregulation in various cancers and the identification of downstream kinases involved in mediating the effects of PI3-K/AKT pathway such as the mammalian target of rapamycin (mTOR), pyruvate dehydrogenase kinase 1 (PDK1) and integrin-linked kinase (ILK) provide potential targets for the development of small molecule therapies. Presently, PI3-K/AKT pathway inhibitors are being studied extensively for their radiosensitization properties. Moreover, strong and independent associations have been found between expression of activated AKT (pAKT) and treatment outcome in clinical trials [49],[108] . The AKT signal transduction pathway is appealing target for therapeutic intervention, because AKT signalling promotes the three major radioresistance mechanisms (i.e. cell survival, tumour cell proliferation and hypoxia) [62],[88],[92] . Therefore, modulation of AKT signalling pathway may have major implications in the radiotherapeutic management especially in tumours that have activated PI3-K/AKT cascade. Inhibition of the pathway can induce apoptosis or sensitize tumour cells to undergo apoptosis in response to radiation therapy. Extensive in vitro and in vivo studies have shown that AKT signalling pathway plays an important role in radiation resistance, targeting this pathway to identify drugs that counteract radiation induced cellular defence mechanisms would be logical [92],[109],[110],[111],[112] . It has been shown that PI3-K/AKT pathway is selectively activated in human cancer cells and sparing the normal cells, suggesting that factors in this cascade are potential molecular target to improve radiosensitivity [113] . Because of the differential activation of this pathway in tumour cells vs. the normal cells, strategies to block PI3-K/AKT signalling should result in more effective radiation treatment by enhancing the sensitivity of tumour cells to radiation vis-a-vis sparing normal tissues surrounding the tumour [109],[113] . However, the problem has been to identify inhibitors of this pathway that are suitable for clinical use. For example, in vitro studies by Gupta et al[113] have shown that LY294002 and wortmannin are potent PI3-K inhibitors with significant radiosensitizing effects but their poor in vivo tolerability limits their clinical applications. Currently, the research is being aimed to develop drugs targeting the PI3-K/AKT pathway that are clinically safe. In this context, HIV protease inhibitors have been shown to inhibit AKT phosphorylation and thus radiosensitize tumour cells at concentrations used for anti-HIV treatment. These drugs have been used for over a decade to treat patients with HIV infection and are considered safe for oral use.

HIV protease inhibitors (HPI) as radiosensitizers: mechanism of radiosensitization

The mechanism of radiosensitization is a combination of proteosome inhibition, induction of cell stress, influence on cell signalling cascades, and autophagy [110] . HPIs are selective peptidomimetic, protease inhibitors that bind with high affinity to the active site of HIV protease. The radiosensitizing property of HPIs mainly relates to the inhibition of proteosome which is responsible for degradation of proteins [114] . These compounds inhibit the 20S ribosome which in turn results in endoplasmic reticulum stress triggering the unfolded protein response (UPR) which activates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) by phosphorylation. The activation of elf2α increases the production of growth arrest and DNA damage-inducible protein (GADD34) which forms a complex with protein phosphatase 1 and induces the downregulation of Phospho-AKT [Figure 1] [114] . The AKT2 isoform, regulates the growth of and metabolism of cells by the insulin/insulin like growth factor signalling pathway [115],[116] . This explains some of the adverse effects of HIV protease inhibitors including hyperlipidaemia, insulin resistance, peripheral lipoatrophy, central fat accumulation, and hepatic steatosis. It is possible that the insulin resistance caused by nelfinavir could be related to the decrease in Akt phosphorylation [113]. An alternate downstream event of inhibition of proteosome leads to stabilization of IκB cellular inhibitory protein of NF-kappa B[110] . This results in inactivation of NF-Kappa B leading to apoptosis, reduced tumour cell survival and, therefore, enhanced radiosensitivity [117]. Additionally, AKT dephosphorylation also inactivates HIF-1α and VEGF leading to enhanced tumour oxygenation and inhibition of neoangiogenesis [92],[118] . This indirectly enhances tumour sensitivity to irradiation [Figure 1].
Figure 1. Mechanisms by which HIV protease inhibitors (HPIs) enhance radiosensitivity. Nelfinavir and other HPIs induce endoplasmic reticulum (ER) stress resulting in unfolded protein response (UPR) which leads to phosphorylation of eukaryotic initiation factor 2 α (eIf2α) leading to global inhibition of protein synthesis and reduced tumour cell survival. A second mechanism is by activation of growth arrest and DNA damage-inducible protein (GADD 34) and protein phosphatase1 (PP1) complex that dephosphorylates phospho-AKT to AKT resulting in decreased DNA replication and increased radiosensitivity. Dephosphorylation of AKT also reduces expression of hypoxia inducible factor (HIF1α) and vascular endothelial growth factor f (VEGF) leading to increased tumour cell oxygenation and decreased angiogenesis which indirectly contributes to enhanced radiosensitivity of the tumour. The third mechanism is by inactivation of nuclear factor Kappa-light-chain-enhancer of activated B cells (NF-kB) which leads to apoptosis and reduced tumour cell survival and thereby indirectly enhancing radiosensitivity. Dephosphorylation of pAKT also activates proapoptotic proteins and inactivates antiapoptotic proteins resulting in activation of apoptotic pathway. Adapted and reproduced from Figure of Ref. 114 with permission from publisher, Taylor and Francis

Click here to view

Extensive in vitro experiments using Western blot assays and clonogenic assays have shown the potential radiosensitive activity of different classes of HPIs in different cancer cell lines [Table II]. The results of the in vitro experiments were further corroborated in in vivo mouse xenograft models using the same class of HPIs [109] .
Table II. Cancer cell line studies using nelfinavir (NFV) as radiosensitizer

Click here to view

Preclinical evidence has shown that HIV protease inhibitors downregulate AKT at dose range that is clinically used for HIV patients. At this dose range, the safety profile of HPIs has been established clinically as well. The HPIs specifically target the tumour tissue only and this makes them the lead compounds to be used as AKT inhibitors and, therefore, as radiosensitizers. Compared to traditional conventional chemotherapy drugs that are used as radiosensitizers, these drugs can be administered orally with high bioavailability, thereby improving patient compliance.

Nelfinavir - the lead HPI as a radiosensitizer

The radiosensitizing ability of HPIs was first shown in HIV positive patients in whom the peripheral blood leukocytes phospho-AKT levels were downregulated [119] . Patients taking these "active" radiosensitizing protease inhibitors had very low levels of phospho-AKT compared to HIV +ve patients taking either no medications or other antiretroviral regimens [119] . This led to extensive studies (both in vitro and in vivo) of different classes of HIV protease inhibitors to determine the mechanistic basis of radiation sensitization. Gupta et al[109] studied the radiosensitizing ability of five different classes of HPIs (nelfinavir, amprenavir, sequinavir, ritonavir and indinavir) against different cancer cell lines and normal cells (fibroblasts) both in vitro as well as in vivo. They observed that three of the five HPIs (saquinavir, amprenavir and nelfinavir) showed potent inhibition of 473 serine AKT phosphorylation in the cancer cell lines but not in the normal rat fibroblasts. Nelfinavir, amprenavir and saquinavir were also shown to radiosensitize human umbilical vein endothelial cells (HUVEC) and tumour vascular endothelium along with inhibition of angiogenesis and tumour cell migration [120] . Of the three HPIs, nelfinavir had more profound effect on HUVEC and tumour vascular endothelium. In vitro pharmacokinetic studies done on SQ20B (head and neck cancer) and T24 (bladder cancer) have shown that low concentration (5 micromol/l) of nelfinavir was enough to downregulate pAKT in comparison to saquinavir and amprenavir (10 micromol/l) [109] . Additionally, nelfinavir was found to be least toxic among all the HPIs, thus making it a lead AKT inhibitor for clinical use as a radiosensitizing agent. The most common side effect of this drug is diarrhoea occurring in 30 per cent patients [121] which is usually mild to moderate and controlled with over the counter antidiarrhoeal drugs. Hyperlipidaemia, hyperglycemia and elevation of transaminases (especially in patients with hepatitis B and C infection due to immune reconstitution) have been reported with long term use of nelfinavir [122] . [Table II] summarizes the mechanism of radiosensitization of nelfinavir in different cancer cell lines.

In vivo studies have shown that the oral bioavailability of nelfinavir is 70-80 per cent in fed state. Food increases nelfinavir exposure and decreases nelfinavir pharmacokinetic variability relative to the fasted state. Exposure to nelfinavir is 2-5 fold higher in fed state compared to fasting state. Nelfinavir exposure increases with increasing calorie or fat content of meals. The drug is extensively bound to plasma proteins (>98%) with a plasma half-life of 3.5-5 h. The majority of an oral dose is excreted in the faeces as oxidative metabolites. Only 1-2 per cent of the drug is excreted unchanged through the kidneys.

Clinical trials of nelfinavir as radiosensitizer

With the availability of preclinical data (in vitro & in vivo) of nelfinavir as a potent radiosensitizing agent, various phase-I and phase-II clinical trials have been initiated. First phase-I clinical trial using nelfinavir was carried out against locally advanced pancreatic cancer. This study showed that the toxicity of nelfinavir along with chemoradiation (radiation dose of 59.4 Gy + gemcitabine and cisplatin) was low with favourable tumour response (metabolic complete response 'CR' in 56% patients) [124] . Another phase-I study of nelfinavir with concurrent chemoradiation (radiation dose of 66.6Gy +cisplatin and etoposide) in stage IIIA/IIIB non-small cell lung cancer (NSCLC) showed acceptable toxicity and promising activity in patients with locally advanced NSCLC (metabolic CR in 56% patients and partial response in 44%) [125] . Recently, a third phase-I study of nelfinavir in combination with capecitabine in rectal cancer (radiation dose of 50.4 Gy) showed promising results with acceptable toxicity and a pathological complete response of 33 per cent [126] . Till date, only these three studies have reported the results of radiation therapy with concomitant nelfinavir along with conventional chemotherapy as radiosensitizer in clinical settings [124],[125],[126] . Both clinical trials have reported grade 3-4 haematologic toxicities attributable to chemotherapy drugs (cisplatin, etoposide and gemcitabine used in these trials). The rectal cancer study had grade-3 lower gastrointestinal (GI) toxicity in the form of diarrhoea. However, all the patients in these three trials could complete their planned treatment. Grade 1 and 2 toxicities were reported in almost all the patients, especially hyperglycaemia, elevated transaminases and lower GI toxicities which were transient and self-limiting. Currently, numerous clinical trials are in progress to test nelfinavir as a radiosensitizer. The details of the clinical trials are summarized in [Table III]. Although the present clinical evidence is still immature, the results of these clinical trials are eagerly awaited to see if nelfinavir actually has the potential to be put into clinical use as a radiosensitizer for various cancers.
Table III. Clinical trials using concurrent nelfinavir and chemotherapy as radiosensitizing agent in HIV seronegative malignant tumours

Click here to view


The role of AKT in cancer has been a subject of discussion over the past decade. It is clear that activation of the AKT pathway is one of the most common molecular alterations in human malignancy conferring to radioresistance thereby providing a strong rationale for targeting the AKT pathway as radiosensitizers. The use of commercially available drugs such as the HPIs is an initial step towards targeting the AKT pathway and these need to be used in clinical radiotherapy trials along with conventional drugs to enhance radiosensitivity of tumours.

Although the complete mechanism of action of HPIs as radiosensitizing agent is not yet completely understood, its broad spectrum of activity, minimal toxicity, and its availability in clinics has made these compounds to be used in cancer therapeutics as a radiosensitizer. Extensive preclinical evidence and ongoing phase-I clinical trials support the use of HPIs with radiation where the effects could be monitored in the patients. Moreover, the tolerability of these compounds has been documented which makes them ideal to be tested in future phase-II and phase-III studies as radiosensitizers.

Conflicts of Interest: None.

   References Top

Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003; 362 : 933-40.  Back to cited text no. 1
Haslett K, Pottgen C, Stuschke M, Faivre-Finn C: Hyperfractionated and accelerated radiotherapy in non-small cell lung cancer. J Thorac Dis 2014; 6 : 328-35.  Back to cited text no. 2
Motegi A, Kawashima M, Arahira S, Zenda S, Toshima M, Onozawa M, et al. Accelerated radiotherapy for T1 to T2 glottic cancer. Head Neck 2015; 37 : 579-84.  Back to cited text no. 3
Gupta T, Kannan S, Ghosh-Laskar S, Agarwal JP. Concomitant chemo-radiotherapy (CT-RT) versus altered fractionation radiotherapy in the radiotherapeutic management of locoregionally advanced head and neck squamous cell carcinoma (HNSCC): an adjusted indirect comparison meta-analysis. Head Neck 2015; 37 : 670-6.  Back to cited text no. 4
Chitapanarux I, Tharavichitkul E, Kamnerdsupaphon P, Pukanhapan N, Vongtama R. Randomized phase III trial of concurrent chemoradiotherapy vs accelerated hyperfractionation radiotherapy in locally advanced head and neck cancer. J Radiat Res 2013; 54 : 1110-7.  Back to cited text no. 5
Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al; MACH-CH Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother o0 ncol 2011; 100 : 33-40.  Back to cited text no. 6
Pignon JP, le Maitre A, Maillard E, Bourhis J; MACH-CH Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009; 92 : 4-14.  Back to cited text no. 7
Green J, Kirwan J, Tierney J, Symonds P, Fresco L, Williams C, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2001 (4): CD002225.  Back to cited text no. 8
Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, et al. Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J c0 lin o0 ncol 2005; 23 : 79-87.  Back to cited text no. 9
Hassan Metwally MA, Ali R, Kuddu M, Shouman T, Strojan P, Iqbal K, et al. IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol 2015; 116 : 15-20.  Back to cited text no. 10
Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck - a systematic review and meta-analysis. Radiother Oncol 2011; 100 : 22-32.  Back to cited text no. 11
Toustrup K, Sorensen BS, Lassen P, Wiuf C, Alsner J, Overgaard J; Danish Head and Neck Cancer Group (DAHANCA). Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol 2012; 102 : 122-9.  Back to cited text no. 12
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New Engl J Med 2006; 354 : 567-78.  Back to cited text no. 13
Heiduschka G, Grah A, Oberndorfer F, Seemann R, Kranz A, Kornek G, et al. Significance of p16 expression in head and neck cancer patients treated with radiotherapy and cetuximab. Strahlenther Onkol 2014; 190 : 832-8.  Back to cited text no. 14
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. New Engl j0 m0 ed 2005; 353 : 123-32.  Back to cited text no. 15
Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366 : 1527-37.  Back to cited text no. 16
Horiike A, Yamamoto N, Tanaka H, Yanagitani N, Kudo K, Ohyanagi F, et al. Phase II study of erlotinib for acquired resistance to gefitinib in patients with advanced non-small cell lung cancer. Anticancer Res 2014; 34 : 1975-81.  Back to cited text no. 17
Genova C, Rijavec E, Barletta G, Burrafato G, Biello F, Dal Bello MG, et al. Afatinib for the treatment of advanced non-small-cell lung cancer. Expert Opin Pharmacother 2014; 15 : 889-903.  Back to cited text no. 18
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21 : 60-5.  Back to cited text no. 19
Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23 : 3697-705.  Back to cited text no. 20
Ponnurangam S, Standing D, Rangarajan P, Subramaniam D. Tandutinib inhibits the Akt/mTOR signaling pathway to inhibit colon cancer growth. Mol Cancer Ther 2013; 12 : 598-609.  Back to cited text no. 21
Li HF, Kim JS, Waldman T. Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells. Radiat o0 ncol 2009; 4 : 1-10.  Back to cited text no. 22
Ringel MD, Hayre N, Saito J, Saunier B, Schuppert F, Burch H, et al. Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res 2001; 61 : 6105-11.  Back to cited text no. 23
Miyakawa M, Tsushima T, Murakami H, Wakai K, Isozaki O, Takano K. Increased expression of phosphorylated p70S6 kinase and Akt in papillary thyroid cancer tissues. Endoc j0 2003; 50 : 77-83.  Back to cited text no. 24
Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L, et al. Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 2001; 61 : 2194-9.  Back to cited text no. 25
Alkan S, Izban KF. Immunohistochemical localization of phosphorylated AKT in multiple myeloma. Blood 2002; 99 : 2278-9.  Back to cited text no. 26
Tanno S, Yanagawa N, Habiro A, Koizumi K, Nakano Y, Osanai M, et al. Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer r0 es 2004; 64 : 3486-90.  Back to cited text no. 27
Nam SY, Lee HS, Jung GA, Choi J, Cho SJ, Kim MK, et al. Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis. APMIS 2003; 111 : 1105-13.  Back to cited text no. 28
Cedres S, Montero MA, Martinez P, Martinez A, Rodriguez-Freixinos V, Torrejon D, et al. Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM). Lung Cancer 2012; 77 : 192-8.  Back to cited text no. 29
Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 2003; 17 : 995-7.  Back to cited text no. 30
Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, et al. The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J c0 lin o0 ncol 2004; 22 : 1926-33.  Back to cited text no. 31
Jiang Z, Pore N, Cerniglia GJ, Mick R, Georgescu MM, Bernhard EJ, et al. Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res 2007; 67 : 4467-73.  Back to cited text no. 32
Blackhall FH, Pintilie M, Michael M, Leighl N, Feld R, Tsao MS, et al. Expression and prognostic significance of kit, protein kinase B, and mitogen-activated protein kinase in patients with small cell lung cancer. Clin Cancer Res 2003; 9 : 2241-7.  Back to cited text no. 33
Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 2002; 23 : 201-5.  Back to cited text no. 34
Gupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, et al. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin c0 ancer r0 es 2002; 8 : 885-92.  Back to cited text no. 35
Lim J, Kim JH, Paeng JY, Kim MJ, Hong SD, Lee JI, et al. Prognostic value of activated Akt expression in oral squamous cell carcinoma. J Clin Pathol 2005; 58 : 1199-205.  Back to cited text no. 36
Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto A, Wang H, et al. Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004; 25 : 2053-9.  Back to cited text no. 37
Tsao AS, McDonnell T, Lam S, Putnam JB, Bekele N, Hong WK, et al. Increased phospho-AKT (Ser(473)) expression in bronchial dysplasia: implications for lung cancer prevention studies. Cancer Epidemiol Biomarkers Prev 2003; 12 : 660-4.  Back to cited text no. 38
Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK, et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 2004; 23 : 5853-7.  Back to cited text no. 39
Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer J 1995; 64 : 280-5.  Back to cited text no. 40
Yuan ZQ, Sun M, Feldman RI, Wang G, Ma X, Jiang C, et al. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene 2000; 19 : 2324-30.  Back to cited text no. 41
Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 1996; 93 : 3636-41.  Back to cited text no. 42
Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev 2005; 24 : 273-85.  Back to cited text no. 43
Yang Y, Ikezoe T, Takeuchi T, Adachi Y, Ohtsuki Y, Takeuchi S, et al. HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling. Cancer s0 ci 2005; 96 : 425-33.  Back to cited text no. 44
Horiguchi A, Oya M, Uchida A, Marumo K, Murai M. Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma. J Urol 2003; 169 : 710-3.  Back to cited text no. 45
Xu X, Sakon M, Nagano H, Hiraoka N, Yamamoto H, Hayashi N, et al. Akt2 expression correlates with prognosis of human hepatocellular carcinoma. Oncol r0 ep 2004; 11 : 25-32.  Back to cited text no. 46
Terakawa N, Kanamori Y, Yoshida S. Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer. Endocr- r0 elat c0 ancer 2003; 10 : 203-8.  Back to cited text no. 47
Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S, et al. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 2004; 23 : 3999-4006.  Back to cited text no. 48
Kim TJ, Lee JW, Song SY, Choi JJ, Choi CH, Kim BG, et al. Increased expression of pAKT is associated with radiation resistance in cervical cancer. Br j0 c0 ancer 2006; 94 : 1678-82.  Back to cited text no. 49
Musat M, Korbonits M, Kola B, Borboli N, Hanson MR, Nanzer AM, et al. Enhanced protein kinase B/Akt signalling in pituitary tumours. Endocri- Relat Cancer 2005; 12 : 423-33.  Back to cited text no. 50
Zeng J, See AP, Aziz K, Thiyagarajan S, Salih T, Gajula RP, et al. Nelfinavir induces radiation sensitization in pituitary adenoma cells. Cancer Biol Therapy 2011; 12 : 657-63.  Back to cited text no. 51
Dent P, Yacoub A, Contessa J, Caron R, Amorino G, Valerie K, et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat r0 es 2003; 159 : 283-300.  Back to cited text no. 52
Meads MB, Gatenby RA, Dalton WS. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 2009; 9 : 665-74.  Back to cited text no. 53
Fodale V, Pierobon M, Liotta L, Petricoin E. Mechanism of cell adaptation: when and how do cancer cells develop chemoresistance? Cancer J 2011; 17 : 89-95.  Back to cited text no. 54
Toulany M, Baumann M, Rodemann HP. Stimulated PI3K-AKT signaling mediated through ligand or radiation-induced EGFR depends indirectly, but not directly, on constitutive K-Ras activity. Mol c0 ancer r0 es 2007; 5 : 863-72.  Back to cited text no. 55
Saki M, Toulany M, Rodemann HP. Acquired resistance to cetuximab is associated with the overexpression of Ras family members and the loss of radiosensitization in head and neck cancer cells. Radiother o0 ncol 2013; 108 : 473-8.  Back to cited text no. 56
Minjgee M, Toulany M, Kehlbach R, Giehl K, Rodemann HP. K-RAS(V12) induces autocrine production of EGFR ligands and mediates radioresistance through EGFR-dependent Akt signaling and activation of DNA-PKcs. Int J Radiat Oncol Biol Phys 2011; 81 : 1506-14.  Back to cited text no. 57
Affolter A, Drigotas M, Fruth K, Schmidtmann I, Brochhausen C, Mann WJ, et al. Increased radioresistance via G12S K-Ras by compensatory upregulation of MAPK and PI3K pathways in epithelial cancer. Head Neck 2013; 35 : 220-8.  Back to cited text no. 58
Kim EJ, Jeong JH, Bae S, Kang S, Kim CH, Lim YB. mTOR inhibitors radiosensitize PTEN-deficient non-small-cell lung cancer cells harboring an EGFR activating mutation by inducing autophagy. J c0 ell Biochem 2013; 114 : 1248-56.  Back to cited text no. 59
Christensen M, Najy AJ, Snyder M, Movilla LS, Kim HR. A critical role of the PTEN/PDGF signaling network for the regulation of radiosensitivity in adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 2014; 88 : 151-8.  Back to cited text no. 60
Rosser CJ, Tanaka M, Pisters LL, Tanaka N, Levy LB, Hoover DC, et al. Adenoviral-mediated PTEN transgene expression sensitizes Bcl-2-expressing prostate cancer cells to radiation. Cancer Gene Ther 2004; 11 : 273-9.  Back to cited text no. 61
Kim IA, Bae SS, Fernandes A, Wu J, Muschel RJ, McKenna WG, et al. Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer r0 es 2005; 65 : 7902-10.  Back to cited text no. 62
Nijkamp MM, Hoogsteen IJ, Span PN, Takes RP, Lok J, Rijken PF, et al. Spatial relationship of phosphorylated epidermal growth factor receptor and activated AKT in head and neck squamous cell carcinoma. Radiother Oncol 2011; 101 : 165-70.  Back to cited text no. 63
Toulany M, Kasten-Pisula U, Brammer I, Wang S, Chen J, Dittmann K, et al. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res 2006; 12 : 4119-26.  Back to cited text no. 64
Park J, Feng J, Li Y, Hammarsten O, Brazil DP, Hemmings BA. DNA-dependent protein kinase-mediated phosphorylation of protein kinase B requires a specific recognition sequence in the C-terminal hydrophobic motif. J Biol Chem 2009; 284 : 6169-74.  Back to cited text no. 65
Toulany M, Lee KJ, Fattah KR, Lin YF, Fehrenbacher B, Schaller M, et al. Akt promotes post-irradiation survival of human tumor cells through initiation, progression, and termination of DNA-PKcs-dependent DNA double-strand break repair. Mol Cancer Res 2012; 10 : 945-57.  Back to cited text no. 66
Bozulic L, Surucu B, Hynx D, Hemmings BA. PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell 2008; 30 : 203-13.  Back to cited text no. 67
Deng R, Tang J, Ma JG, Chen SP, Xia LP, Zhou WJ, et al. PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation. Oncogene 2011; 30 : 944-55.  Back to cited text no. 68
Lavin MF. ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene 2007; 26 : 7749-58.  Back to cited text no. 69
Fraser M, Harding SM, Zhao H, Coackley C, Durocher D, Bristow RG. MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks. Cell Cycle 2011; 10 : 2218-32.  Back to cited text no. 70
Xiang T, Jia Y, Sherris D, Li S, Wang H, Lu D, et al. Targeting the Akt/mTOR pathway in Brca1-deficient cancers. Oncogene 2011; 30 : 2443-50.  Back to cited text no. 71
Plo I, Laulier C, Gauthier L, Lebrun F, Calvo F, Lopez BS. AKT1 inhibits homologous recombination by inducing cytoplasmic retention of BRCA1 and RAD51. Cancer Res 2008; 68 : 9404-12.  Back to cited text no. 72
Jia Y, Song W, Zhang F, Yan J, Yang Q. Akt1 inhibits homologous recombination in Brca1-deficient cells by blocking the Chk1-Rad51 pathway. Oncogene 2013; 32 : 1943-9.  Back to cited text no. 73
Toulany M, Minjgee M, Saki M, Holler M, Meier F, Eicheler W, et al. ERK2-dependent reactivation of Akt mediates the limited response of tumor cells with constitutive K-RAS activity to PI3K inhibition. Cancer b0 iol t0 her 2014; 15 : 317-28.  Back to cited text no. 74
Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res 2008; 68 : 1485-94.  Back to cited text no. 75
Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 2010; 120 : 127-41.  Back to cited text no. 76
Chaachouay H, Ohneseit P, Toulany M, Kehlbach R, Multhoff G, Rodemann HP. Autophagy contributes to resistance of tumor cells to ionizing radiation. Radiother Oncol 2011; 99 : 287-92.  Back to cited text no. 77
Fujiwara K, Daido S, Yamamoto A, Kobayashi R, Yokoyama T, Aoki H, et al. Pivotal role of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in apoptosis and autophagy. J Biol Chem 2008; 283 : 388-97.  Back to cited text no. 78
Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer 2005; 5 : 516-25.  Back to cited text no. 79
Schmidt-Ullrich RK, Mikkelsen RB, Dent P, Todd DG, Valerie K, Kavanagh BD, et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 1997; 15 : 1191-7.  Back to cited text no. 80
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2 : 489-501.  Back to cited text no. 81
Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003; 17 : 590-603.  Back to cited text no. 82
Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell cycle 2003; 2 : 339-45.  Back to cited text no. 83
Harris AL. Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2 : 38-47.  Back to cited text no. 84
Koumenis C. ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 2006; 6 : 55-69.  Back to cited text no. 85
Bussink J, Kaanders JH, van der Kogel AJ. Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother Oncol 2003; 67 : 3-15.  Back to cited text no. 86
Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, et al. Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 2001; 93 : 1337-43.  Back to cited text no. 87
Pore N, Gupta AK, Cerniglia GJ, Maity A. HIV protease inhibitors decrease VEGF/HIF-1alpha expression and angiogenesis in glioblastoma cells. Neoplasia 2006; 8 : 889-95.  Back to cited text no. 88
Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 2008; 9 : 288-96.  Back to cited text no. 89
Schuurbiers OC, Kaanders JH, van der Heijden HF, Dekhuijzen RP, Oyen WJ, Bussink J. The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer. J Thorac Oncol 2009; 4 : 761-7.  Back to cited text no. 90
Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 2011; 4 : 51.  Back to cited text no. 91
Pore N, Gupta AK, Cerniglia GJ, Jiang Z, Bernhard EJ, Evans SM, et al. Nelfinavir down-regulates hypoxia-inducible factor 1alpha and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res 2006; 66 : 9252-9.  Back to cited text no. 92
Zhu Y, Denhardt DT, Cao H, Sutphin PD, Koong AC, Giaccia AJ, et al. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene 2005; 24 : 6555-63.  Back to cited text no. 93
Dai J, Peng L, Fan K, Wang H, Wei R, Ji G, et al. Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells. Oncogene 2009; 28 : 3412-22.  Back to cited text no. 94
Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer r0 es 2001; 61 : 6020-4.  Back to cited text no. 95
Fokas E, Im JH, Hill S, Yameen S, Stratford M, Beech J, et al. Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature. Cancer r0 es 2012; 72 : 239-48.  Back to cited text no. 96
Morelli MP, Cascone T, Troiani T, Tuccillo C, Bianco R, Normanno N, et al. Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases. J Cell Physiol 2006; 208 : 344-53.  Back to cited text no. 97
Mabeta P. Inhibition of phosphoinositide 3-kinase is associated with reduced angiogenesis and an altered expression of angiogenic markers in endothelioma cells. Biomed Pharmacother 2014; 68 : 611-7.  Back to cited text no. 98
Warburg O. On the origin of cancer cells. Science 1956; 123 : 309-14.  Back to cited text no. 99
Weber G. Enzymology of cancer cells (second of two parts). New Engl J Med 1977; 296 : 541-51.  Back to cited text no. 100
Weber G. Enzymology of cancer cells (first of two parts). New Engl J Med 1977; 296 : 486-92.  Back to cited text no. 101
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004; 64 : 3892-9.  Back to cited text no. 102
Kim DI, Lim SK, Park MJ, Han HJ, Kim GY, Park SH. The involvement of phosphatidylinositol 3-kinase /Akt signaling in high glucose-induced downregulation of GLUT-1 expression in ARPE cells. Life Sci 2007; 80 : 626-32.  Back to cited text no. 103
Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 2008; 15 : 521-9.  Back to cited text no. 104
Deprez J, Vertommen D, Alessi DR, Hue L, Rider MH. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J0 b0 iol c0 hem 1997; 272 : 17269-75.  Back to cited text no. 105
Simons AL, Orcutt KP, Madsen JM, Scarbrough PM, Spitz DR. The role of AKt pathway signalling in glucose metabolism and metabolic oxidative stress. In: Spitz DR, Dornfeld KJ, Krishnan K, Gius D, editors. Oxidative stress in cancer biology and therapy. New York: Springer Science & Business Media; 2012. p. 21-46.  Back to cited text no. 106
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30 : 193-204.  Back to cited text no. 107
Ocana A, Vera-Badillo F, Al-Mubarak M, Templeton AJ, Corrales-Sanchez V, Diez-Gonzalez L, et al. Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis. PLoS One 2014; 9 : e95219.  Back to cited text no. 108
Gupta AK, Cerniglia GJ, Mick R, McKenna WG, Muschel RJ. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res 2005; 65 : 8256-65.  Back to cited text no. 109
Russo SM, Tepper JE, Baldwin AS Jr, Liu R, Adams J, Elliott P, et al. Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. Int j0 r0 adiat o0 ncol, b0 iol, p0 hy 2001; 50 : 183-93.  Back to cited text no. 110
Gupta AK, Lee JH, Wilke WW, Quon H, Smith G, Maity A, et al. Radiation response in two HPV-infected head-and-neck cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling through AKT. Int J Radiat Oncol Bio Phy 2009; 74 : 928-33.  Back to cited text no. 111
Pajonk F, Himmelsbach J, Riess K, Sommer A, McBride WH. The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res 2002; 62 : 5230-5.  Back to cited text no. 112
Gupta AK, Li B, Cerniglia GJ, Ahmed MS, Hahn SM, Maity A. The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Neoplasia 2007; 9 : 271-8.  Back to cited text no. 113
Bernhard EJ, Brunner TB. Progress towards the use of HIV protease inhibitors in cancer therapy. Cancer b0 iol T0 her 2008; 7 : 636-7.  Back to cited text no. 114
Bae SS, Cho H, Mu J, Birnbaum MJ. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem 2003; 278 : 49530-6.  Back to cited text no. 115
Cross DA, Watt PW, Shaw M, van der Kaay J, Downes CP, Holder JC, et al. Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-insensitive pathways in skeletal muscle and adipose tissue. FEBS Lett 1997; 406 : 211-5.  Back to cited text no. 116
Kariya R, Taura M, Suzu S, Kai H, Katano H, Okada S. HIV protease inhibitor Lopinavir induces apoptosis of primary effusion lymphoma cells via suppression of NF-kappaB pathway. Cancer Lett 2014; 342 : 52-9.  Back to cited text no. 117
Birle DC, Hedley DW. Suppression of the hypoxia-inducible factor-1 response in cervical carcinoma xenografts by proteasome inhibitors. Cancer Res 2007; 67 : 1735-43.  Back to cited text no. 118
Plastaras JP, Vapiwala N, Ahmed MS, Gudonis D, Cerniglia GJ, Feldman MD, et al. Validation and toxicity of PI3K/Akt pathway inhibition by HIV protease inhibitors in humans. Cancer Biol Ther 2008; 7 : 628-35.  Back to cited text no. 119
Cuneo KC, Tu T, Geng L, Fu A, Hallahan DE, Willey CD. HIV protease inhibitors enhance the efficacy of irradiation. Cancer Res 2007; 67 : 4886-93.  Back to cited text no. 120
Tebas P, Powderly WG. Nelfinavir mesylate. Expert Opin Pharmacother 2000; 1 : 1429-40.  Back to cited text no. 121
Ofotokun I, Smithson SE, Lu C, Easley KA, Lennox JL. Liver enzymes elevation and immune reconstitution among treatment-naive HIV-infected patients instituting antiretroviral therapy. Am J Med Sci 2007; 334 : 334-41.  Back to cited text no. 122
Pyrko P, Kardosh A, Wang W, Xiong W, Schonthal AH, Chen TC. HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer Res 2007; 67 : 10920-8.  Back to cited text no. 123
Brunner TB, Geiger M, Grabenbauer GG, Lang-Welzenbach M, Mantoni TS, Cavallaro A, et al. Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer. J Clin Oncol 2008; 26 : 2699-706.  Back to cited text no. 124
Rengan R, Mick R, Pryma D, Rosen MA, Lin LL, Maity AM, et al. A phase I trial of the HIV protease inhibitor nelfinavir with concurrent chemoradiotherapy for unresectable stage IIIA/IIIB non-small cell lung cancer: a report of toxicities and clinical response. J Thorac Oncol 2012; 7 : 709-15.  Back to cited text no. 125
Buijsen J, Lammering G, Jansen RL, Beets GL, Wals J, Sosef M, et al. Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer. Radiother Oncol 2013; 107 : 184-8.  Back to cited text no. 126


  [Figure 1]

  [Table I], [Table II], [Table III]

This article has been cited by
1 Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer
Arlene E. Garcia-Soto,Nathalie D. McKenzie,Margaret E. Whicker,Joseph M. Pearson,Edward A. Jimenez,Lorraine Portelance,Jennifer J. Hu,Joseph A. Lucci,Rehman Qureshi,Andrew Kossenkov,Lauren Schwartz,Gordon B. Mills,Amit Maity,Lilie L. Lin,Fiona Simpkins
Cancer. 2021;
[Pubmed] | [DOI]
2 New drugs are not enough-drug repositioning in oncology: An update
Romina Armando,Diego Mengual G?mez,Daniel Gomez
International Journal of Oncology. 2020;
[Pubmed] | [DOI]
3 The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir
Mahbuba R. Subeha,Carlos M. Telleria
Cancers. 2020; 12(11): 3437
[Pubmed] | [DOI]
4 Modulation of mTORC1 Signaling Pathway by HIV-1
Burkitkan Akbay,Anna Shmakova,Yegor Vassetzky,Svetlana Dokudovskaya
Cells. 2020; 9(5): 1090
[Pubmed] | [DOI]
5 The radiobiology of HPV-positive and HPV-negative head and neck squamous cell carcinoma
Chumin Zhou,Jason L. Parsons
Expert Reviews in Molecular Medicine. 2020; 22
[Pubmed] | [DOI]
6 HIV-1, HAART and cancer: A complex relationship
Anna Shmakova,Diego Germini,Yegor Vassetzky
International Journal of Cancer. 2019;
[Pubmed] | [DOI]
7 What patents tell us about drug repurposing for cancer: A landscape analysis
Hermann A.M. Mucke
Seminars in Cancer Biology. 2019;
[Pubmed] | [DOI]
8 The Novel Roles of Connexin Channels and Tunneling Nanotubes in Cancer Pathogenesis
Silvana Valdebenito,Emil Lou,John Baldoni,George Okafo,Eliseo Eugenin
International Journal of Molecular Sciences. 2018; 19(5): 1270
[Pubmed] | [DOI]
9 Radiotherapy in patients with HIV: current issues and review of the literature
Filippo Alongi,Niccolò Giaj-Levra,Savino Sciascia,Alessandra Fozza,Sergio Fersino,Alba Fiorentino,Rosario Mazzola,Francesco Ricchetti,Michela Buglione,Dora Buonfrate,Dario Roccatello,Umberto Ricardi,Zeno Bisoffi
The Lancet Oncology. 2017; 18(7): e379
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded396    
    Comments [Add]    
    Cited by others 9    

Recommend this journal