Abstract
Arsenic, a naturally-occurring toxic element, and a traditionally-used drug, has received a great deal of attention worldwide due to its curative anti-cancer properties in patients with acute promyelocytic leukemia. Among the arsenicals, arsenic trioxide has been most widely used as an anti-cancer drug. Recent advances in cancer therapeutics have led to a paradigm shift away from traditional cytotoxic drugs towards the targeting of proteins closely associated with driving the cancer phenotype. Due to the diverse anti-cancer effects of ATO on different types of malignancies, numerous studies have made efforts to uncover the mechanisms of ATO-induced tumor suppression. From in vitro cellular models to studies in clinical settings, ATO has been extensively studied. The outcomes of these studies have opened doors to establishing improved molecular-targeted therapies for cancer treatment. The efficacy of ATO has been augmented by combination with other drugs. In this review, we discuss recent arsenic-based cancer therapies and summarize the novel underlying molecular mechanisms of the anti-cancer effects of ATO.
Keywords: Arsenic, anti-cancer drug, chemotherapy, apoptosis, reactive oxygen species, acute promyelocytic leukemia.
Graphical Abstract
[http://dx.doi.org/10.1634/theoncologist.6-suppl_2-3] [PMID: 11331434]
[PMID: 11610136]
[http://dx.doi.org/10.1016/S0140-6736(13)62120-0] [PMID: 25484026]
[http://dx.doi.org/10.1038/nrc887] [PMID: 12209159]
[http://dx.doi.org/10.1038/sj.leu.2402599] [PMID: 12200700]
[http://dx.doi.org/10.1007/s00775-018-1537-9] [PMID: 29396610]
[http://dx.doi.org/10.4172/1948-5956.1000432] [PMID: 28966729]
[http://dx.doi.org/10.1371/journal.pone.0174591] [PMID: 28355296]
[http://dx.doi.org/10.3892/or.2015.3890] [PMID: 25845556]
[http://dx.doi.org/10.1007/s13277-016-5377-3] [PMID: 27677289]
[http://dx.doi.org/10.1007/s13277-010-0111-z] [PMID: 20857258]
[http://dx.doi.org/10.1016/j.yexcr.2010.04.027] [PMID: 20435036]
[http://dx.doi.org/10.1097/00006676-200308000-00011] [PMID: 12883267]
[http://dx.doi.org/10.2147/OTT.S49148] [PMID: 23990729]
[http://dx.doi.org/10.3892/ijo.2014.2609] [PMID: 25174355]
[http://dx.doi.org/10.2174/1568009614666140725090000] [PMID: 25088040]
[PMID: 10477740]
[http://dx.doi.org/10.3892/ijo.2015.2826] [PMID: 25572414]
[PMID: 27158399]
[http://dx.doi.org/10.18632/oncotarget.17100] [PMID: 28467781]
[http://dx.doi.org/10.3748/wjg.v12.i36.5780] [PMID: 17007042]
[http://dx.doi.org/10.1186/1477-7819-8-31] [PMID: 20403207]
[http://dx.doi.org/10.1371/journal.pone.0054774] [PMID: 23382965]
[http://dx.doi.org/10.1016/j.ygyno.2006.02.037] [PMID: 16624393]
[http://dx.doi.org/10.1371/journal.pone.0020586] [PMID: 21655183]
[http://dx.doi.org/10.1038/cdd.2010.53] [PMID: 20508647]
[http://dx.doi.org/10.1016/j.febslet.2012.11.003] [PMID: 23178716]
[http://dx.doi.org/10.1073/pnas.0701549104] [PMID: 17640917]
[http://dx.doi.org/10.1158/1078-0432.CCR-10-0068] [PMID: 20519360]
[http://dx.doi.org/10.3390/ijms13089627] [PMID: 22949821]
[http://dx.doi.org/10.1371/journal.pone.0035957] [PMID: 22558281]
[http://dx.doi.org/10.1038/nature03552] [PMID: 15944707]
[http://dx.doi.org/10.1038/nrc1840] [PMID: 16557279]
[http://dx.doi.org/10.1016/j.molonc.2012.09.006] [PMID: 23102669]
[http://dx.doi.org/10.1002/mc.22157] [PMID: 24729530]
[http://dx.doi.org/10.1080/15384101.2017.1387699] [PMID: 28980872]
[http://dx.doi.org/10.1177/1010428317692255] [PMID: 28218039]
[http://dx.doi.org/10.1007/s12032-008-9105-8] [PMID: 18937079]
[http://dx.doi.org/10.1002/jcb.24230] [PMID: 22730174]
[http://dx.doi.org/10.1016/j.toxlet.2014.08.024] [PMID: 25196641]
[http://dx.doi.org/10.1016/j.toxlet.2014.03.016] [PMID: 24680928]
[http://dx.doi.org/10.1093/toxsci/kfu218] [PMID: 25304214]
[http://dx.doi.org/10.3892/mmr.2016.4757] [PMID: 26781180]
[PMID: 11454688]
[PMID: 26966376]
[http://dx.doi.org/10.1111/cas.12548] [PMID: 25283513]
[http://dx.doi.org/10.3892/or.2012.1719] [PMID: 22426647]
[http://dx.doi.org/10.1371/journal.pone.0054398] [PMID: 23342147]
[http://dx.doi.org/10.1016/S0304-3835(02)00039-3] [PMID: 12430174]
[http://dx.doi.org/10.1097/CAD.0b013e32834f1fd3] [PMID: 22245994]
[http://dx.doi.org/10.1016/j.bbrc.2014.08.014] [PMID: 25117446]
[http://dx.doi.org/10.1016/j.ygyno.2007.04.016] [PMID: 17512576]
[http://dx.doi.org/10.1002/ijc.20433] [PMID: 15382040]
[http://dx.doi.org/10.1002/jcp.21470] [PMID: 18412143]
[http://dx.doi.org/10.1097/IGC.0b013e31821d2525] [PMID: 21792014]
[http://dx.doi.org/10.4161/cbt.10.6.12654] [PMID: 20657188]
[http://dx.doi.org/10.1245/s10434-014-3812-5] [PMID: 25047463]
[http://dx.doi.org/10.3892/or.10.6.1869] [PMID: 14534710]
[http://dx.doi.org/10.1016/j.canlet.2011.12.005] [PMID: 22155346]
[http://dx.doi.org/10.1002/hed.21535] [PMID: 20737493]
[http://dx.doi.org/10.1016/j.bbrc.2006.07.181] [PMID: 16904648]
[http://dx.doi.org/10.1016/j.bbrc.2007.06.123] [PMID: 17617380]
[http://dx.doi.org/10.1016/j.canlet.2011.06.035] [PMID: 21788103]
[PMID: 23977542]
[http://dx.doi.org/10.1002/jcp.22397] [PMID: 20799280]
[http://dx.doi.org/10.3892/ijo.2014.2716] [PMID: 25335113]
[http://dx.doi.org/10.1038/sj.onc.1208095] [PMID: 15592527]
[http://dx.doi.org/10.1016/j.canlet.2008.03.019] [PMID: 18439752]
[http://dx.doi.org/10.1007/s00401-007-0243-4] [PMID: 17618441]
[http://dx.doi.org/10.1016/j.canlet.2009.11.005] [PMID: 19962820]
[http://dx.doi.org/10.18632/oncotarget.5836] [PMID: 26510911]
[http://dx.doi.org/10.18632/oncotarget.7259] [PMID: 26871293]
[http://dx.doi.org/10.1371/journal.pone.0069466] [PMID: 23861973]
[http://dx.doi.org/10.1002/ijc.29107] [PMID: 25082385]
[http://dx.doi.org/10.3892/ol.2017.6347] [PMID: 28789348]
[http://dx.doi.org/10.1182/blood-2007-07-102798] [PMID: 18299451]
[http://dx.doi.org/10.1038/ncb1716] [PMID: 18408734]
[http://dx.doi.org/10.1038/ncb1717] [PMID: 18408733]
[http://dx.doi.org/10.1126/science.1183424] [PMID: 20378816]
[http://dx.doi.org/10.1074/jbc.M800560200] [PMID: 18482988]
[http://dx.doi.org/10.1002/jcb.20337] [PMID: 15547942]
[PMID: 10850458]
[PMID: 12492118]
[http://dx.doi.org/10.1182/blood-2002-10-3231] [PMID: 12531793]
[http://dx.doi.org/10.1038/sj.onc.1208484] [PMID: 15735709]
[http://dx.doi.org/10.1182/blood-2007-10-116889] [PMID: 18354037]
[http://dx.doi.org/10.1371/journal.pone.0032215] [PMID: 22384180]
[PMID: 10029061]
[PMID: 20164031]
[http://dx.doi.org/10.1073/pnas.1016311108] [PMID: 21118980]
[http://dx.doi.org/10.3892/or.2014.3369] [PMID: 25110043]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-1532] [PMID: 25316819]
[http://dx.doi.org/10.3892/or.2017.5945] [PMID: 28901456]
[http://dx.doi.org/10.1038/leu.2016.311] [PMID: 27795556]
[PMID: 18575716]
[PMID: 15354410]
[http://dx.doi.org/10.1016/j.bcp.2006.07.026] [PMID: 16950207]
[PMID: 18636201]
[http://dx.doi.org/10.1016/j.lungcan.2008.01.002] [PMID: 18281123]
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0287] [PMID: 18645016]
[http://dx.doi.org/10.1038/sj.onc.1208192] [PMID: 15531921]
[PMID: 18695917]
[http://dx.doi.org/10.1371/journal.pone.0031579] [PMID: 22363680]
[http://dx.doi.org/10.4161/auto.5.4.7759] [PMID: 19242099]
[http://dx.doi.org/10.4161/auto.6.3.11229] [PMID: 20200477]
[http://dx.doi.org/10.1667/RR2380.1] [PMID: 21388295]
[PMID: 21455570]
[PMID: 18596414]
[http://dx.doi.org/10.1016/j.fct.2014.02.039] [PMID: 24632069]
[http://dx.doi.org/10.1186/1471-2407-14-27] [PMID: 24428916]
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0409] [PMID: 17145888]
[http://dx.doi.org/10.1007/s13402-014-0167-7] [PMID: 24599717]
[http://dx.doi.org/10.1186/1756-9966-28-110] [PMID: 19664237]
[http://dx.doi.org/10.1111/j.1349-7006.2009.01340.x] [PMID: 19769630]
[http://dx.doi.org/10.1016/j.canlet.2018.06.027] [PMID: 29944906]
[http://dx.doi.org/10.1182/blood-2005-06-2318] [PMID: 16249384]
[http://dx.doi.org/10.1186/s12935-015-0158-4] [PMID: 25698901]
[http://dx.doi.org/10.1038/nm.1891] [PMID: 19029980]
[http://dx.doi.org/10.1038/sj.leu.2403923] [PMID: 16107885]
[http://dx.doi.org/10.1080/10428194.2017.1289522] [PMID: 28276286]
[http://dx.doi.org/10.1182/blood-2014-11-612416] [PMID: 25800051]
[http://dx.doi.org/10.1002/ijc.28427] [PMID: 23934954]
[PMID: 9864171]
[http://dx.doi.org/10.1038/sj.leu.2404797] [PMID: 17568816]
[http://dx.doi.org/10.1016/0092-8674(93)80044-F] [PMID: 8394219]
[PMID: 3165295]
[http://dx.doi.org/10.1182/blood-2008-04-150250] [PMID: 18812465]
[http://dx.doi.org/10.1182/blood-2005-08-3532] [PMID: 16352810]
[http://dx.doi.org/10.1200/JCO.2001.19.18.3852] [PMID: 11559723]
[http://dx.doi.org/10.1093/jnci/90.2.124] [PMID: 9450572]
[http://dx.doi.org/10.1073/pnas.0400053101] [PMID: 15044693]
[PMID: 9129042]
[http://dx.doi.org/10.1056/NEJMoa1300874] [PMID: 23841729]
[http://dx.doi.org/10.1111/j.1600-0609.2008.01079.x] [PMID: 18363868]
[http://dx.doi.org/10.1182/blood-2009-03-211821] [PMID: 19411628]
[http://dx.doi.org/10.3324/haematol.10703] [PMID: 17488707]
[http://dx.doi.org/10.1080/02841860601042456] [PMID: 17497326]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2590] [PMID: 20501625]
[PMID: 12473574]
[http://dx.doi.org/10.18632/oncotarget.14733] [PMID: 28108741]
[http://dx.doi.org/10.1021/ic401211u] [PMID: 24147771]
[http://dx.doi.org/10.1200/JCO.2005.10.217] [PMID: 15800332]
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0045] [PMID: 19567824]
[http://dx.doi.org/10.1002/anie.201303251] [PMID: 24038962]
[http://dx.doi.org/10.1021/jacs.8b13681] [PMID: 30943017]
[http://dx.doi.org/10.1016/j.ijpharm.2017.01.031] [PMID: 28109899]
[http://dx.doi.org/10.1007/s00277-017-3163-y] [PMID: 29159499]