{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T20:37:22Z","timestamp":1787603842592,"version":"build-2736575974"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2017,10,5]],"date-time":"2017-10-05T00:00:00Z","timestamp":1507161600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,10,5]],"date-time":"2017-10-05T00:00:00Z","timestamp":1507161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Autophagy promotes cancer cell survival and drug resistance by degrading harmful cellular components and maintaining cellular energy levels. Disruption of autophagy may be a promising approach to sensitize cancer cells to anticancer drugs. The combination of autophagic inhibitors, such as chloroquine (CQ) and lucanthone with conventional cancer therapeutics has been investigated in clinical trials, but adverse drug\u2013drug interactions are a high possibility. Here we designed and synthesized a novel, small-molecule library based on an acridine skeleton and the CQ structure with various modifications and substitutions and screened the compounds for effective autophagy inhibition. We found that 9-chloro-2-(3-(dimethylamino)propyl)pyrrolo[2,3,4-kl]acridin-1(2H)-one (LS-1-10) was the most effective from our library at inhibiting autophagic-mediated degradation and could decrease the viability of multiple colon cancer cells. In addition, LS-1-10 induced DNA damage and caspase 8-mediated apoptosis. Overall, this small molecule was more efficient at reducing the viability of cancer cells than other conventional chemotherapeutic agents, such as CQ and amsacrine. The anticancer and autophagy-inhibiting activities of LS-1-10 were confirmed <jats:italic>in vivo<\/jats:italic> in a xenograft mouse model. Collectively, this study has identified a new and efficient single compound with both autophagy-inhibiting and anticancer activity, which may provide a novel approach for cancer therapy.<\/jats:p>","DOI":"10.1038\/cddis.2017.498","type":"journal-article","created":{"date-parts":[[2017,10,5]],"date-time":"2017-10-05T12:43:29Z","timestamp":1507207409000},"page":"e3086-e3086","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["A novel acridine derivative, LS-1-10 inhibits autophagic degradation and triggers apoptosis in colon cancer cells"],"prefix":"10.1038","volume":"8","author":[{"given":"Wan","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopeng","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbao","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-6581","authenticated-orcid":false,"given":"Wei-Guo","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,5]]},"reference":[{"key":"BFcddis2017498_CR1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nature14190","volume":"517","author":"A Efeyan","year":"2015","unstructured":"Efeyan A, Comb WC, Sabatini DM . Nutrient-sensing mechanisms and pathways. Nature 2015; 517: 302\u2013310.","journal-title":"Nature"},{"key":"BFcddis2017498_CR2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nrm4024","volume":"16","author":"J Kaur","year":"2015","unstructured":"Kaur J, Debnath J . Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 2015; 16: 461\u2013472.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFcddis2017498_CR3","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.molcel.2010.09.023","volume":"40","author":"G Kroemer","year":"2010","unstructured":"Kroemer G, Marino G, Levine B . Autophagy and the integrated stress response. Molecular cell 2010; 40: 280\u2013293.","journal-title":"Molecular cell"},{"key":"BFcddis2017498_CR4","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/ncb0910-823","volume":"12","author":"N Mizushima","year":"2010","unstructured":"Mizushima N, Levine B . Autophagy in mammalian development and differentiation. Nat Cell Biol 2010; 12: 823\u2013830.","journal-title":"Nat Cell Biol"},{"key":"BFcddis2017498_CR5","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1146\/annurev-genet-102808-114910","volume":"43","author":"C He","year":"2009","unstructured":"He C, Klionsky DJ . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67\u201393.","journal-title":"Annu Rev Genet"},{"key":"BFcddis2017498_CR6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cell.2014.02.049","volume":"157","author":"DR Green","year":"2014","unstructured":"Green DR, Levine B . To be or not to be? How selective autophagy and cell death govern cell fate. Cell 2014; 157: 65\u201375.","journal-title":"Cell"},{"key":"BFcddis2017498_CR7","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","volume":"147","author":"N Mizushima","year":"2011","unstructured":"Mizushima N, Komatsu M . Autophagy: renovation of cells and tissues. Cell 2011; 147: 728\u2013741.","journal-title":"Cell"},{"key":"BFcddis2017498_CR8","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/446745a","volume":"446","author":"B Levine","year":"2007","unstructured":"Levine B . Cell biology: autophagy and cancer. Nature 2007; 446: 745\u2013747.","journal-title":"Nature"},{"key":"BFcddis2017498_CR9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","volume":"132","author":"B Levine","year":"2008","unstructured":"Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell 2008; 132: 27\u201342.","journal-title":"Cell"},{"key":"BFcddis2017498_CR10","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/ncb2069","volume":"12","author":"Y Zhao","year":"2010","unstructured":"Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 2010; 12: 665\u2013675.","journal-title":"Nat Cell Biol"},{"key":"BFcddis2017498_CR11","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/sj.cdd.4401359","volume":"11","author":"T Kanzawa","year":"2004","unstructured":"Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S . Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004; 11: 448\u2013457.","journal-title":"Cell Death Differ"},{"key":"BFcddis2017498_CR12","first-page":"2103","volume":"63","author":"T Kanzawa","year":"2003","unstructured":"Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I . Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 2003; 63: 2103\u20132108.","journal-title":"Cancer Res"},{"key":"BFcddis2017498_CR13","first-page":"439","volume":"61","author":"S Paglin","year":"2001","unstructured":"Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E et al. A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 2001; 61: 439\u2013444.","journal-title":"Cancer Res"},{"key":"BFcddis2017498_CR14","doi-asserted-by":"crossref","first-page":"18030","DOI":"10.1073\/pnas.0408345102","volume":"101","author":"Y Shao","year":"2004","unstructured":"Shao Y, Gao Z, Marks PA, Jiang X . Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA 2004; 101: 18030\u201318035.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2017498_CR15","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/onc.2009.343","volume":"29","author":"K Zhu","year":"2010","unstructured":"Zhu K, Dunner K Jr., McConkey DJ . Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene 2010; 29: 451\u2013462.","journal-title":"Oncogene"},{"key":"BFcddis2017498_CR16","doi-asserted-by":"crossref","first-page":"464","DOI":"10.4161\/auto.4311","volume":"3","author":"JS Carew","year":"2007","unstructured":"Carew JS, Nawrocki ST, Cleveland JL . Modulating autophagy for therapeutic benefit. Autophagy 2007; 3: 464\u2013467.","journal-title":"Autophagy"},{"key":"BFcddis2017498_CR17","first-page":"1269","volume":"10","author":"KM Livesey","year":"2009","unstructured":"Livesey KM, Tang D, Zeh HJ, Lotze MT . Autophagy inhibition in combination cancer treatment. Curr Opin Invest Drugs 2009; 10: 1269\u20131279.","journal-title":"Curr Opin Invest Drugs"},{"key":"BFcddis2017498_CR18","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1172\/JCI28833","volume":"117","author":"RK Amaravadi","year":"2007","unstructured":"Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117: 326\u2013336.","journal-title":"J Clin Invest"},{"key":"BFcddis2017498_CR19","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/0014-4800(87)90018-9","volume":"47","author":"H Glaumann","year":"1987","unstructured":"Glaumann H, Ahlberg J . Comparison of different autophagic vacuoles with regard to ultrastructure, enzymatic composition, and degradation capacity\u2014formation of crinosomes. Exp Mol Pathol 1987; 47: 346\u2013362.","journal-title":"Exp Mol Pathol"},{"key":"BFcddis2017498_CR20","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/leu.2014.349","volume":"29","author":"AR Sehgal","year":"2015","unstructured":"Sehgal AR, Konig H, Johnson DE, Tang D, Amaravadi RK, Boyiadzis M et al. You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia. Leukemia 2015; 29: 517\u2013525.","journal-title":"Leukemia"},{"key":"BFcddis2017498_CR21","first-page":"292","volume":"23","author":"HN Bernstein","year":"1991","unstructured":"Bernstein HN . Ocular safety of hydroxychloroquine. Ann Ophthalmol 1991; 23: 292\u2013296.","journal-title":"Ann Ophthalmol"},{"key":"BFcddis2017498_CR22","first-page":"1183","volume":"68","author":"RH Creech","year":"1984","unstructured":"Creech RH, Tritchler D, Ettinger DS, Ferraro JA, Ruckdeschel JC, Vogl SE et al. Phase II study of PALA, amsacrine, teniposide, and zinostatin in small cell lung carcinoma (EST 2579). Cancer Treat Rep 1984; 68: 1183\u20131184.","journal-title":"Cancer Treat Rep"},{"key":"BFcddis2017498_CR23","doi-asserted-by":"crossref","first-page":"13682","DOI":"10.1021\/bi00041a050","volume":"34","author":"JM Crenshaw","year":"1995","unstructured":"Crenshaw JM, Graves DE, Denny WA . Interactions of acridine antitumor agents with DNA: binding energies and groove preferences. Biochemistry 1995; 34: 13682\u201313687.","journal-title":"Biochemistry"},{"key":"BFcddis2017498_CR24","first-page":"989","volume":"68","author":"CS Kao-Shan","year":"1984","unstructured":"Kao-Shan CS, Micetich K, Zwelling LA, Whang-Peng J . Cytogenetic effects of amsacrine on human lymphocytes in vivo and in vitro. Cancer Treat Rep 1984; 68: 989\u2013997.","journal-title":"Cancer Treat Rep"},{"key":"BFcddis2017498_CR25","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2174\/0929867023369277","volume":"9","author":"WA Denny","year":"2002","unstructured":"Denny WA . Acridine derivatives as chemotherapeutic agents. Curr Med Chem 2002; 9: 1655\u20131665.","journal-title":"Curr Med Chem"},{"key":"BFcddis2017498_CR26","first-page":"923","volume":"68","author":"PC Amrein","year":"1984","unstructured":"Amrein PC, Richards F 2nd, Coleman M, Poulin RF, Holland JF, Weinberg V et al. Phase II trial of amsacrine in patients with hepatoma: a Cancer and Leukemia Group B study. Cancer Treat Rep 1984; 68: 923\u2013924.","journal-title":"Cancer Treat Rep"},{"key":"BFcddis2017498_CR27","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/0277-5379(84)90212-8","volume":"20","author":"VH Bramwell","year":"1984","unstructured":"Bramwell VH, Holdener EE, Siegenthaler P, Ten Bokkel Huinink W, Bruntsch U, Renard J et al. Phase II study of amsacrine in refractory lymphomas. A report of the EORTC Early Clinical Trials Group. Eur J Cancer Clin Oncol 1984; 20: 753\u2013759.","journal-title":"Eur J Cancer Clin Oncol"},{"key":"BFcddis2017498_CR28","first-page":"1051","volume":"68","author":"B De Bernardi","year":"1984","unstructured":"De Bernardi B, Pastore G, Garaventa A, Calculli G, Carli M, Ceci A et al. Phase II trial of amsacrine in children with advanced metastatic neuroblastoma. Cancer Treat Rep 1984; 68: 1051\u20131052.","journal-title":"Cancer Treat Rep"},{"key":"BFcddis2017498_CR29","first-page":"1411","volume":"68","author":"M Inamasu","year":"1984","unstructured":"Inamasu M, Oishi N, Chen T, Legha S, McCracken J, Balcerzak S et al. Phase II trial of amsacrine in pancreatic carcinoma: a Southwest Oncology Group study. Cancer Treat Rep 1984; 68: 1411\u20131412.","journal-title":"Cancer Treat Rep"},{"key":"BFcddis2017498_CR30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.2174\/0929867053363414","volume":"12","author":"R Martinez","year":"2005","unstructured":"Martinez R, Chacon-Garcia L . The search of DNA-intercalators as antitumoral drugs: what it worked and what did not work. Curr Med Chem 2005; 12: 127\u2013151.","journal-title":"Curr Med Chem"},{"key":"BFcddis2017498_CR31","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1038\/onc.2011.168","volume":"30","author":"S Shen","year":"2011","unstructured":"Shen S, Kepp O, Michaud M, Martins I, Minoux H, Metivier D et al. Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study. Oncogene 2011; 30: 4544\u20134556.","journal-title":"Oncogene"},{"key":"BFcddis2017498_CR32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","volume":"12","author":"DJ Klionsky","year":"2016","unstructured":"Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016; 12: 1\u2013222.","journal-title":"Autophagy"},{"key":"BFcddis2017498_CR33","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.cell.2007.10.035","volume":"131","author":"M Komatsu","year":"2007","unstructured":"Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 2007; 131: 1149\u20131163.","journal-title":"Cell"},{"key":"BFcddis2017498_CR34","doi-asserted-by":"crossref","first-page":"24131","DOI":"10.1074\/jbc.M702824200","volume":"282","author":"S Pankiv","year":"2007","unstructured":"Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H et al. p62\/SQSTM1 binds directly to Atg8\/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 2007; 282: 24131\u201324145.","journal-title":"J Biol Chem"},{"key":"BFcddis2017498_CR35","doi-asserted-by":"crossref","first-page":"8055","DOI":"10.1128\/MCB.24.18.8055-8068.2004","volume":"24","author":"ML Seibenhener","year":"2004","unstructured":"Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW . Sequestosome 1\/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 2004; 24: 8055\u20138068.","journal-title":"Mol Cell Biol"},{"key":"BFcddis2017498_CR36","doi-asserted-by":"crossref","first-page":"6783","DOI":"10.1074\/jbc.M709496200","volume":"283","author":"MW Wooten","year":"2008","unstructured":"Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N et al. Essential role of sequestosome 1\/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J Biol Chem 2008; 283: 6783\u20136789.","journal-title":"J Biol Chem"},{"key":"BFcddis2017498_CR37","doi-asserted-by":"crossref","first-page":"452","DOI":"10.4161\/auto.4451","volume":"3","author":"S Kimura","year":"2007","unstructured":"Kimura S, Noda T, Yoshimori T . Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 2007; 3: 452\u2013460.","journal-title":"Autophagy"},{"key":"BFcddis2017498_CR38","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1152\/physrev.00030.2009","volume":"90","author":"B Ravikumar","year":"2010","unstructured":"Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010; 90: 1383\u20131435.","journal-title":"Physiol Rev"},{"key":"BFcddis2017498_CR39","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nrm2217","volume":"8","author":"JP Luzio","year":"2007","unstructured":"Luzio JP, Pryor PR, Bright NA . Lysosomes: fusion and function. Nat Rev Mol Cell Biol 2007; 8: 622\u2013632.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFcddis2017498_CR40","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrm2745","volume":"10","author":"P Saftig","year":"2009","unstructured":"Saftig P, Klumperman J . Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 2009; 10: 623\u2013635.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFcddis2017498_CR41","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.bbapap.2011.05.013","volume":"1824","author":"V Kaminskyy","year":"2012","unstructured":"Kaminskyy V, Zhivotovsky B . Proteases in autophagy. Biochim Biophys Acta 2012; 1824: 44\u201350.","journal-title":"Biochim Biophys Acta"},{"key":"BFcddis2017498_CR42","doi-asserted-by":"crossref","first-page":"6434","DOI":"10.1038\/onc.2008.310","volume":"27","author":"P Boya","year":"2008","unstructured":"Boya P, Kroemer G . Lysosomal membrane permeabilization in cell death. Oncogene 2008; 27: 6434\u20136451.","journal-title":"Oncogene"},{"key":"BFcddis2017498_CR43","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/bs.aihch.2015.04.004","volume":"115","author":"A Schmidt","year":"2015","unstructured":"Schmidt A, Liu M . Recent advances in the chemistry of acridines. Adv Heterocycl Chem 2015; 115: 287\u2013353.","journal-title":"Adv Heterocycl Chem"},{"key":"BFcddis2017498_CR44","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nrc2607","volume":"9","author":"JL Nitiss","year":"2009","unstructured":"Nitiss JL . Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 2009; 9: 338\u2013350.","journal-title":"Nat Rev Cancer"},{"key":"BFcddis2017498_CR45","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1038\/sj.onc.1207532","volume":"23","author":"CJ Norbury","year":"2004","unstructured":"Norbury CJ, Zhivotovsky B . DNA damage-induced apoptosis. Oncogene 2004; 23: 2797\u20132808.","journal-title":"Oncogene"},{"key":"BFcddis2017498_CR46","doi-asserted-by":"crossref","first-page":"6602","DOI":"10.1074\/jbc.M110.151324","volume":"286","author":"JS Carew","year":"2011","unstructured":"Carew JS, Espitia CM, Esquivel JA 2nd, Mahalingam D, Kelly KR, Reddy G et al. Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem 2011; 286: 6602\u20136613.","journal-title":"J Biol Chem"},{"key":"BFcddis2017498_CR47","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/S0006-2952(99)00221-X","volume":"58","author":"L Dassonneville","year":"1999","unstructured":"Dassonneville L, Bailly C . Stimulation of topoisomerase II-mediated DNA cleavage by an indazole analogue of lucanthone. Biochem Pharmacol 1999; 58: 1307\u20131312.","journal-title":"Biochem Pharmacol"},{"key":"BFcddis2017498_CR48","first-page":"2127","volume":"24","author":"M Luo","year":"2004","unstructured":"Luo M, Kelley MR . Inhibition of the human apurinic\/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone. Anticancer Res 2004; 24: 2127\u20132134.","journal-title":"Anticancer Res"},{"key":"BFcddis2017498_CR49","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/0145-2126(86)90331-0","volume":"10","author":"PA Cassileth","year":"1986","unstructured":"Cassileth PA, Gale RP . Amsacrine: a review. Leuk Res 1986; 10: 1257\u20131265.","journal-title":"Leuk Res"},{"key":"BFcddis2017498_CR50","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1200\/JCO.1985.3.4.562","volume":"3","author":"AC Louie","year":"1985","unstructured":"Louie AC, Issell BF . Amsacrine (AMSA)\u2014a clinical review. J Clin Oncol 1985; 3: 562\u2013592.","journal-title":"J Clin Oncol"},{"key":"BFcddis2017498_CR51","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/nrc2067","volume":"7","author":"A Albini","year":"2007","unstructured":"Albini A, Sporn MB . The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007; 7: 139\u2013147.","journal-title":"Nat Rev Cancer"},{"key":"BFcddis2017498_CR52","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.2741\/2389","volume":"12","author":"HJ Knowles","year":"2007","unstructured":"Knowles HJ, Harris AL . Macrophages and the hypoxic tumour microenvironment. Front Biosci 2007; 12: 4298\u20134314.","journal-title":"Front Biosci"},{"key":"BFcddis2017498_CR53","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00280-008-0881-9","volume":"63","author":"F Mbeunkui","year":"2009","unstructured":"Mbeunkui F, Johann DJ Jr . Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemother Pharmacol 2009; 63: 571\u2013582.","journal-title":"Cancer Chemother Pharmacol"},{"key":"BFcddis2017498_CR54","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.molcel.2016.05.027","volume":"63","author":"Y Wang","year":"2016","unstructured":"Wang Y, Zhang N, Zhang L, Li R, Fu W, Ma K et al. Autophagy Regulates Chromatin Ubiquitination in DNA Damage Response through Elimination of SQSTM1\/p62. Mol Cell 2016; 63: 34\u201348.","journal-title":"Mol Cell"},{"key":"BFcddis2017498_CR55","doi-asserted-by":"crossref","first-page":"21142","DOI":"10.1074\/jbc.M111.306399","volume":"287","author":"S Conus","year":"2012","unstructured":"Conus S, Pop C, Snipas SJ, Salvesen GS, Simon HU . Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis. J Biol Chem 2012; 287: 21142\u201321151.","journal-title":"J Biol Chem"},{"key":"BFcddis2017498_CR56","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1073\/pnas.0408592102","volume":"102","author":"H Erdal","year":"2005","unstructured":"Erdal H, Berndtsson M, Castro J, Brunk U, Shoshan MC, Linder S . Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. Proc Natl Acad Sci USA 2005; 102: 192\u2013197.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2017498_CR57","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nature09803","volume":"471","author":"T Robert","year":"2011","unstructured":"Robert T, Vanoli F, Chiolo I, Shubassi G, Bernstein KA, Rothstein R et al. HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature 2011; 471: 74\u201379.","journal-title":"Nature"},{"key":"BFcddis2017498_CR58","doi-asserted-by":"crossref","first-page":"891","DOI":"10.4161\/auto.6.7.13038","volume":"6","author":"W Hou","year":"2010","unstructured":"Hou W, Han J, Lu C, Goldstein LA, Rabinowich H . Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy 2010; 6: 891\u2013900.","journal-title":"Autophagy"},{"key":"BFcddis2017498_CR59","first-page":"357","volume":"4","author":"JS Carew","year":"2012","unstructured":"Carew JS, Kelly KR, Nawrocki ST . Autophagy as a target for cancer therapy: new developments. Cancer Manag Res 2012; 4: 357\u2013365.","journal-title":"Cancer Manag Res"},{"key":"BFcddis2017498_CR60","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ejphar.2009.06.063","volume":"625","author":"VR Solomon","year":"2009","unstructured":"Solomon VR, Lee H . Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacology 2009; 625: 220\u2013233.","journal-title":"Eur J Pharmacology"},{"key":"BFcddis2017498_CR61","doi-asserted-by":"crossref","first-page":"8253","DOI":"10.1073\/pnas.1118193109","volume":"109","author":"Q McAfee","year":"2012","unstructured":"McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH, Piao S et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci USA 2012; 109: 8253\u20138258.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2017498_CR62","unstructured":"Meng X, Li Z, Liu S, Yu S, Que L . Fused acridine derivative and pharmaceutical composition, preparation method and use thereof: WO 2015\/127878 A1[P]. 2015-2-15; US patent application US-2017-0015664-A1[P]. 2016-8-22; EU patent application EP3098222(A1)[P]. 2016-8-22; JP patent application 2016-554241[P]. 2016-8-24; AU patent application 2015222590[P]. 2016-8-17. CN 201410065618.6[P]. 2014-2-25."},{"key":"BFcddis2017498_CR63","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","volume":"8","author":"FA Ran","year":"2013","unstructured":"Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F . Genome engineering using the CRISPR-Cas9 system. Nature Protoc 2013; 8: 2281\u20132308.","journal-title":"Nature Protoc"},{"key":"BFcddis2017498_CR64","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ymeth.2009.02.016","volume":"48","author":"W Liao","year":"2009","unstructured":"Liao W, McNutt MA, Zhu WG . The comet assay: a sensitive method for detecting DNA damage in individual cells. Methods 2009; 48: 46\u201353.","journal-title":"Methods"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2017498.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017498","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/cddis.2017.498","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017498.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T18:28:44Z","timestamp":1671733724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2017498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,5]]},"references-count":64,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,10]]}},"alternative-id":["BFcddis2017498"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2017.498","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,5]]},"assertion":[{"value":"23 April 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2017","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2017","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2017","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}