Repurposing loperamide to overcome gefitinib resistance by triggering apoptosis independent of autophagy induction in KRAS mutant NSCLC cells

Sharma, 2007, Epidermal growth factor receptor mutations in lung cancer, Nature Reviews Cancer, 7, 169, 10.1038/nrc2088 Lynch, 2004, Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, New England J Medicine, 350, 2129, 10.1056/NEJMoa040938 Paez, 2004, EGFR mutations in lung, cancer: correlation with clinical response to gefitinib therapy, Science, 304, 1497, 10.1126/science.1099314 Morgillo, 2016, Mechanisms of resistance to EGFR-targeted drugs: lung cancer, ESMO Open, 1, 10.1136/esmoopen-2016-000060 Tong, 2017, Drug combination approach to overcome resistance to EGFR tyrosine kinase inhibitors in lung cancer, Cancer Lett., 405, 100, 10.1016/j.canlet.2017.07.023 Gozuacik, 2004, Autophagy as a cell death and tumor suppressor mechanism, Oncogene, 23, 2891, 10.1038/sj.onc.1207521 Tsujimoto, 2005, Another way to die: autophagic programmed cell death, Cell Death Differ., 12, 1528, 10.1038/sj.cdd.4401777 Gorzalczany, 2011, Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: a beneficial strategy to combat non-small cell lung cancer, Cancer Lett., 310, 207, 10.1016/j.canlet.2011.07.002 Zhao, 2016, Gefitinib induces lung cancer cell autophagy and apoptosis via blockade of the PI3K/AKT/mTOR pathway, Oncol Lett, 12, 63, 10.3892/ol.2016.4606 Li, 2013, Erlotinib-induced autophagy in epidermal growth factor receptor mutated non-small cell lung cancer, Lung Cancer, 81, 354, 10.1016/j.lungcan.2013.05.012 Hippert, 2006, Autophagy in cancer: good, bad, or both?, Cancer Res., 66, 9349, 10.1158/0008-5472.CAN-06-1597 White, 2009, The double-edged sword of autophagy modulation in cancer, Clinical Cancer Research, 15, 5308, 10.1158/1078-0432.CCR-07-5023 Galluzzi, 2015, Autophagy in malignant transformation and cancer progression, EMBO J., 34, 856, 10.15252/embj.201490784 Moreau, 2010, Cytoprotective roles for autophagy, Curr. Opin. Cell Biol., 22, 206, 10.1016/j.ceb.2009.12.002 Hu, 2012, Tumor cell autophagy as an adaptive response mediating resistance to treatments such as antiangiogenic therapy, Cancer Res., 72, 4294, 10.1158/0008-5472.CAN-12-1076 Li, 2010, Roles of autophagy in cetuximab-mediated cancer therapy against EGFR, Autophagy, 6, 1066, 10.4161/auto.6.8.13366 Yoo, 2010, Oncogenic ras-induced down-regulation of autophagy mediator Beclin-1 is required for malignant transformation of intestinal epithelial cells, J Biological Chemistry, 285, 5438, 10.1074/jbc.M109.046789 Elgendy, 2011, Oncogenic ras-induced expression of noxa and beclin-1 promotes autophagic cell death and limits clonogenic survival, Mol. Cell, 42, 23, 10.1016/j.molcel.2011.02.009 Shin, 2013, Overexpression of beclin1 induced autophagy and apoptosis in lungs of K-rasLA1 mice, Lung Cancer, 81, 362, 10.1016/j.lungcan.2013.05.009 Chen, 2019, Curcumin overcome primary gefitinib resistance in non-small-cell lung cancer cells through inducing autophagy-related cell death, J Experimental and Clinical Cancer Research, 38, 254, 10.1186/s13046-019-1234-8 Renna, 2010, Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases, J Biological Chemistry, 285, 11061, 10.1074/jbc.R109.072181 Zielke, 2018, Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells, Cell Death and Disease, 9, 994, 10.1038/s41419-018-1003-1 Juárez, 2016, Loperamide restricts intracellular growth of Mycobacterium tuberculosis in lung macrophages, Am. J. Respir. Cell Mol. Biol., 55, 837, 10.1165/rcmb.2015-0383OC Skehan, 1990, New colorimetric cytotoxicity assay for anticancer-drug screening, J. Natl. Cancer Inst., 82, 1107, 10.1093/jnci/82.13.1107 Chou, 1984, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors, Adv. Enzyme Regul., 22, 27, 10.1016/0065-2571(84)90007-4 Yang, 2013, Application and interpretation of current autophagy inhibitors and activators, Acta Pharmacol. Sin., 34, 625, 10.1038/aps.2013.5 Gump, 2011, Autophagy and apoptosis: what is the connection?, Trends Cell Biol., 21, 387, 10.1016/j.tcb.2011.03.007 Hotta, 2007, Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation, Oncol. Rep., 17, 313 Sequist, 2008, First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations, J Clinical Oncology, 26, 2442, 10.1200/JCO.2007.14.8494 Sahani, 2014, Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids, Autophagy, 10, 431, 10.4161/auto.27344 Levine, 2019, Biological Functions of Autophagy Genes: a Disease Perspective, Cell, 176, 11, 10.1016/j.cell.2018.09.048 Janse van Rensburg, 2019, Autophagy in plants: both a puppet and a puppet master of sugars, Front Plant Sci, 10, 14, 10.3389/fpls.2019.00014 Hirsh, 2014, Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors, Current Oncology, 21, 329, 10.3747/co.21.2241 Pushpakom, 2018, Drug repurposing: progress, challenges and recommendations, Nature Reviews Drug Discovery, 18, 41, 10.1038/nrd.2018.168 el Osta, 2019, Characteristics and outcomes of patients with metastatic kras-mutant lung adenocarcinomas: the Lung Cancer Mutation Consortium Experience, J Thoracic Oncology, 14, 876, 10.1016/j.jtho.2019.01.020 Holzer, 2009, Opioid receptors in the gastrointestinal tract, Regul. Pept., 155, 11, 10.1016/j.regpep.2009.03.012 Yoshida, 2000, Opioid analgesic-induced apoptosis and caspase-independent cell death in human lung carcinoma A549 cells, Int. J. Mol. Med., 6, 329 Daly, 2000, Loperamide: novel effects on capacitative calcium influx, Cellular and Molecular Life Sciences, 57, 149, 10.1007/s000180050504 Berchtold, 2014, The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer, Biochimica et Biophysica Acta - Molecular Cell Research, 1843, 398, 10.1016/j.bbamcr.2013.10.021 Pushpakom, 2018, Drug repurposing: progress, challenges and recommendations, Nature reviews drug discovery, 18, 41, 10.1038/nrd.2018.168 IMODIUM Label, n.d. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017694s052lbl.pdf (accessed August 3, 2020). Wu, 2014, Thermosensitive hydrogel used in dual drug delivery system with paclitaxel-loaded micelles for in situ treatment of lung cancer, Colloids and Surfaces B: Biointerfaces, 122, 90, 10.1016/j.colsurfb.2014.06.052 el Osta, 2019, Characteristics and outcomes of patients with metastatic kras-mutant lung adenocarcinomas: the Lung Cancer Mutation Consortium Experience, Journal of Thoracic Oncology, 14, 876, 10.1016/j.jtho.2019.01.020 Zheng, 2016, The prevalence and prognostic significance of KRAS mutation subtypes in lung adenocarcinomas from Chinese populations, Onco Targets Ther, 9, 833, 10.2147/OTT.S96834 Yoshizawa, 2013, Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients, J Thoracic Oncology, 8, 52, 10.1097/JTO.0b013e3182769aa8 Román, 2018, KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target, Mol. Cancer, 17, 33, 10.1186/s12943-018-0789-x Eng, 2016, Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy, Proc. Natl. Acad. Sci. U.S.A., 113, 182, 10.1073/pnas.1515617113