{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T05:14:59Z","timestamp":1771737299627,"version":"3.50.1"},"reference-count":49,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T00:00:00Z","timestamp":1556496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Medical Practice Plan (MPP), AUB"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2019,8,15]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tyrosine kinase inhibitors (TKIs) are the standard treatment for chronic myeloid leukemia (CML). Despite their clinical success, TKIs are faced with challenges such as treatment resistance, which may be driven by kinase domain mutations, and frequent disease relapse upon the cessation of treatment. The combination of arsenic trioxide (ATO) and interferon\u2010\u03b1 (IFN) was previously demonstrated to inhibit proliferation and induce apoptosis in CML cell lines, prolong the survival of primary wild\u2010type CML mice, and dramatically decrease the activity of leukemia\u2010initiating cells (LICs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The ATO\/IFN combination was tested in vitro on imatinib (IMN)\u2010resistant K562\u2010R and Ar230\u2010R cells. 3\u2010(4,5\u2010Dimethylthiazol\u20102\u2010yl)\u20102,5\u2010diphenyl tetrazolium bromide and terminal deoxynucleotidyl transferase\u2013mediated deoxyuridine triphosphate nick\u2010end labeling assays were used to evaluate proliferation and apoptosis, respectively. The acridine orange assay was used to assess autophagy, and quantitative reverse transcription\u2013polymerase chain reaction was used to assess the involvement of the hedgehog (Hh) pathway. In vivo, a retroviral transduction\/transplantation T315I\n                      <jats:italic>BCR\u2010ABL<\/jats:italic>\n                      CML mouse model was used to assay the effect of the treatment on survival, tumor burden (histopathology and blood counts), and LIC activity (secondary transplantation).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In vitro, ATO\/IFN synergized to inhibit proliferation and induce apoptosis of IMN\u2010resistant cells with variant modes of resistance. Furthermore, the preclinical effects of ATO\/IFN were associated with induction of autophagy along with inhibition of the Hh pathway. Most remarkably, ATO\/IFN significantly prolonged the survival of primary T315I\u2010CML mice and displayed a dramatic impairment of disease engraftment in secondary mice, which reflected decreased LIC activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, the ATO\/IFN strategy has been demonstrated to have the potential to lead to durable remissions in TKI\u2010resistant CML preclinical models and to overcome various TKI\u2010specific mechanisms of resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.32130","type":"journal-article","created":{"date-parts":[[2019,4,30]],"date-time":"2019-04-30T21:11:29Z","timestamp":1556658689000},"page":"2818-2828","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Antitumor efficacy of arsenic\/interferon in preclinical models of chronic myeloid leukemia resistant to tyrosine kinase inhibitors"],"prefix":"10.1002","volume":"125","author":[{"given":"Rabab","family":"El Eit","sequence":"first","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiological Sciences American University of Beirut Beirut Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul Rahman","family":"Itani","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiological Sciences American University of Beirut Beirut Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farah","family":"Nassar","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiological Sciences American University of Beirut Beirut Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nagham","family":"Rasbieh","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiological 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