The HIV protease and PI3K/Akt inhibitor nelfinavir does not improve the curative effect of fractionated irradiation in PC-3 prostate cancer in vitro and in vivo

Warde, 2011, Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial, Lancet Lond Engl, 378, 2104, 10.1016/S0140-6736(11)61095-7 Franke, 1997, PI3K: downstream AKTion blocks apoptosis, Cell, 88, 435, 10.1016/S0092-8674(00)81883-8 Datta, 1999, Cellular survival: a play in three Akts, Genes Dev, 13, 2905, 10.1101/gad.13.22.2905 Contessa, 2002, Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells, Oncogene, 21, 4032, 10.1038/sj.onc.1205500 Gupta, 2001, The Ras radiation resistance pathway, Cancer Res, 61, 4278 Diaz, 2009, The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer, Br J Cancer, 100, 932, 10.1038/sj.bjc.6604938 Potiron, 2013, Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions, Radiother Oncol, 106, 138, 10.1016/j.radonc.2012.11.014 Gills, 2007, Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo, Clin Cancer Res, 13, 5183, 10.1158/1078-0432.CCR-07-0161 Yang, 2005, 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 Sci, 96, 425, 10.1111/j.1349-7006.2005.00063.x Gupta, 2005, HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo, Cancer Res, 65, 8256, 10.1158/0008-5472.CAN-05-1220 Gupta, 2007, The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response, Neoplasia N Y N, 9, 271, 10.1593/neo.07124 Jiang, 2007, Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir, Cancer Res, 67, 4467, 10.1158/0008-5472.CAN-06-3398 Kimple, 2010, Radiosensitization of EGFR/HER2 positive pancreatic cancer is mediated by inhibition of Akt independent of Ras mutational status, Clin Cancer Res Off J Am Assoc Cancer Res, 16, 912, 10.1158/1078-0432.CCR-09-1324 Brunner, 2008, Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer, J Clin Oncol, 26, 2699, 10.1200/JCO.2007.15.2355 Buijsen, 2013, Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer, Radiother Oncol, 107, 184, 10.1016/j.radonc.2013.03.023 Hill, 2016, Clinical trial of oral nelfinavir before and during radiation therapy for advanced rectal cancer, Clin Cancer Res, 10.1158/1078-0432.CCR-15-1489 Rengan, 2012, A phase I trial of the HIV protease inhibitor nelfinavir with concurrent chemoradiotherapy (CT-RT) for unresectable stage IIIA/IIIB NSCLC: a report of toxicities and clinical response, J Thorac Oncol, 7, 709, 10.1097/JTO.0b013e3182435aa6 Guan, 2012, Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer, FEBS J, 279, 2399, 10.1111/j.1742-4658.2012.08619.x Mathur, 2014, Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells, PLoS ONE, 9, e103109, 10.1371/journal.pone.0103109 Grünwald, 2002, Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells, Cancer Res, 62, 6141 Li, 1997, PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer, Science, 275, 1943, 10.1126/science.275.5308.1943 Pore, 2006, Nelfinavir down-regulates hypoxia-inducible factor 1α and VEGF expression and increases tumor oxygenation: implications for radiotherapy, Cancer Res, 66, 9252, 10.1158/0008-5472.CAN-06-1239 Bourré, 2003, Synthesis, and in vitro and in vivo evaluation of a diphenylchlorin sensitizer for photodynamic therapy, J Photochem Photobiol B, 69, 179, 10.1016/S1011-1344(03)00020-4 Hensley, 2011, PKA knockdown enhances cell killing in response to radiation and androgen deprivation, Int J Cancer J Int Cancer, 128, 962, 10.1002/ijc.25634 Kim, 1998, The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors, J Clin Invest, 101, 289, 10.1172/JCI1269 Yaromina, 2011, Exploratory study of the prognostic value of microenvironmental parameters during fractionated irradiation in human squamous cell carcinoma xenografts, Int J Radiat Oncol Biol Phys, 80, 1205, 10.1016/j.ijrobp.2011.02.015 Yang, 2006, NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines, Br J Cancer, 95, 1653, 10.1038/sj.bjc.6603435 Wang, 2006, Identification of differentially transcribed genes in human lymphoblastoid cells irradiated with 0.5Gy of γ-ray and the involvement of low dose radiation inducible CHD6 gene in cell proliferation and radiosensitivity, Int J Radiat Biol, 82, 181, 10.1080/09553000600632261 Polkinghorn, 2013, Androgen receptor signaling regulates DNA repair in prostate cancers, Cancer Discov, 3, 1245, 10.1158/2159-8290.CD-13-0172 Gilbert, 1996, Association of BCL-2 with membrane hyperpolarization and radioresistance, J Cell Physiol, 168, 114, 10.1002/(SICI)1097-4652(199607)168:1<114::AID-JCP14>3.0.CO;2-7 Isohashi, 2008, Insulin-like growth factor stimulation increases radiosensitivity of a pancreatic cancer cell line through endoplasmic reticulum stress under hypoxic conditions, Cancer Sci, 99, 2395, 10.1111/j.1349-7006.2008.00970.x Ikezoe, 2004, HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2, Am Assoc Cancer Res, 3, 473 Yin, 2011, Overexpression of STAT3 potentiates growth, survival, and radioresistance of non-small-cell lung cancer (NSCLC) cells, J Surg Res, 171, 675, 10.1016/j.jss.2010.03.053 Cho, 2002, Downregulation of ERK2 is essential for the inhibition of radiation-induced cell death in HSP25 overexpressed L929 cells, Cell Death Differ, 9, 448, 10.1038/sj.cdd.4400979 Shim, 2012, Selective inhibition of HER2-positive breast cancer cells by the HIV protease inhibitor nelfinavir, J Natl Cancer Inst, 104, 1576, 10.1093/jnci/djs396 Workman, 2007, Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress, Ann N Y Acad Sci, 1113, 202, 10.1196/annals.1391.012 Gradin, 1996, Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor, Mol Cell Biol, 16, 5221, 10.1128/MCB.16.10.5221 Brüning, 2010, Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells, Breast Cancer Res, 12, R45, 10.1186/bcr2602 Brüning, 2012, Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4, Toxicol Appl Pharmacol, 264, 300, 10.1016/j.taap.2012.08.011 Johnson, 2015, Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine, Mol Oncol, 9, 675, 10.1016/j.molonc.2014.11.005