Abstract
Resistance to chemotherapy and relapse are major hurdles for the effective treatment of cancer. Major reason for this is a small sub population of cancer stem cells (CSCs) and its microenvironment. CSCs are critical driving force for several types of cancer, such as gastric, colon, breast and many more. Hence, for the complete eradication of cancer, it is necessary to develop therapeutic approaches that can specifically target CSCs. Chemical agents that target different proteins involved in CSC signaling pathways, either as single agent or simultaneously targeting two or more proteins have generated promising pre-clinical and clinical results. In the current review article, we have discussed various targets and cellular pathways that can be explored for the effective and complete eradication of CSCs. Some latest developments in the field of design, synthesis and screening of ligands to target cancer stem cells have been summarized in the current review article.
Keywords: Cancer stem cells, PI3K/AKT pathway, Wnt Pathway, hedgehog pathway, notch pathway, nuclear factor-kappa-B.
Graphical Abstract
[PMID: 22679565]
[http://dx.doi.org/10.1038/nrc.2017.36] [PMID: 28643779]
[http://dx.doi.org/10.2174/0929867325666171206102501] [PMID: 29210637]
[http://dx.doi.org/10.2174/0929867325666180309112023] [PMID: 29521208]
[http://dx.doi.org/10.1016/j.urolonc.2008.07.009] [PMID: 18818107]
[http://dx.doi.org/10.2174/1389450120666181204165344] [PMID: 30516105]
[http://dx.doi.org/10.1016/j.semcancer.2017.02.007] [PMID: 28254567]
[http://dx.doi.org/10.2174/138920111794295783] [PMID: 21044002]
[PMID: 28393696]
[http://dx.doi.org/10.4252/wjsc.v7.i1.27] [PMID: 25621103]
[http://dx.doi.org/10.1007/s11605-014-2497-1] [PMID: 24643495]
[http://dx.doi.org/10.4161/cc.6.19.4914] [PMID: 17786053]
[http://dx.doi.org/10.1038/aps.2013.27] [PMID: 23685952]
[http://dx.doi.org/10.1016/j.bbcan.2009.11.002]
[http://dx.doi.org/10.1002/stem.2596] [PMID: 28207184]
[http://dx.doi.org/10.1111/cas.12817] [PMID: 26362755]
[http://dx.doi.org/10.1016/j.semcancer.2017.03.003] [PMID: 28323021]
[http://dx.doi.org/10.2174/1568009616666160928110818] [PMID: 27697026]
[http://dx.doi.org/10.3390/ijms20102586] [PMID: 31137762]
[http://dx.doi.org/10.1146/annurev.med.53.082901.103929] [PMID: 11818492]
[http://dx.doi.org/10.1016/j.ejmech.2019.05.018] [PMID: 31100649]
[http://dx.doi.org/10.1016/j.bpc.2018.01.004] [PMID: 29407904]
[http://dx.doi.org/10.1158/1538-7445.AM2016-251]
[http://dx.doi.org/10.1038/nature04957] [PMID: 16810242]
[http://dx.doi.org/10.1038/oncsis.2015.35] [PMID: 26619402]
[http://dx.doi.org/10.2174/1871520615666150716104152] [PMID: 26179271]
[http://dx.doi.org/10.2174/0929867324666171006131927] [PMID: 28990521]
[http://dx.doi.org/10.2174/1574892813666180831102519] [PMID: 30173649]
[http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]
[http://dx.doi.org/10.1007/s00404-014-3377-3] [PMID: 25086744]
[http://dx.doi.org/10.1007/s00428-014-1588-4] [PMID: 24844205]
[http://dx.doi.org/10.1038/nrc3860] [PMID: 25533673]
[http://dx.doi.org/10.1016/j.ctrv.2003.07.007] [PMID: 15023437]
[http://dx.doi.org/10.1038/nrc839] [PMID: 12094235]
[http://dx.doi.org/10.1242/dev.137075] [PMID: 27578176]
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[http://dx.doi.org/10.3389/fonc.2013.00108] [PMID: 23658859]
[http://dx.doi.org/10.1038/nrd4204] [PMID: 24481312]
[http://dx.doi.org/10.1021/jm401138v] [PMID: 24345273]
[http://dx.doi.org/10.1021/ml300309h] [PMID: 24900568]
[http://dx.doi.org/10.1021/acs.jmedchem.7b00357] [PMID: 28409639]
[http://dx.doi.org/10.1021/acsmedchemlett.6b00005] [PMID: 27096040]
[http://dx.doi.org/10.1021/jm3007933] [PMID: 23394126]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00626] [PMID: 26083478]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00627] [PMID: 26102506]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01483] [PMID: 26741947]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00235] [PMID: 27427973]
[http://dx.doi.org/10.1021/jm4003632] [PMID: 23662903]
[http://dx.doi.org/10.1021/ml5005014] [PMID: 25893045]
[http://dx.doi.org/10.1038/bcj.2017.16] [PMID: 28282033]
[http://dx.doi.org/10.1021/acsmedchemlett.6b00209] [PMID: 27774127]
[http://dx.doi.org/10.1021/acsmedchemlett.6b00238] [PMID: 27660692]
[http://dx.doi.org/10.1021/jm501629p] [PMID: 25514658]
[http://dx.doi.org/10.1021/jm301522m] [PMID: 23410005]
[http://dx.doi.org/10.1038/sj.onc.1203245] [PMID: 10630639]
[http://dx.doi.org/10.1074/mcp.RA118.000596] [PMID: 29386236]
[http://dx.doi.org/10.1038/nature03319] [PMID: 15829953]
[http://dx.doi.org/10.1038/nature08356] [PMID: 19759537]
[http://dx.doi.org/10.1021/jm401317z] [PMID: 24294969]
[http://dx.doi.org/10.1021/jm400211f] [PMID: 23672613]
[http://dx.doi.org/10.1021/jm400807n] [PMID: 23844574]
[http://dx.doi.org/10.1021/jm401356t] [PMID: 24527792]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01574] [PMID: 27983846]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00460] [PMID: 26182238]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00223] [PMID: 25985283]
[http://dx.doi.org/10.1021/jm501436m] [PMID: 25680029]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00597] [PMID: 27490956]
[http://dx.doi.org/10.2174/0929867324666170316115500] [PMID: 28302010]
[http://dx.doi.org/10.1242/dev.083691] [PMID: 25183867]
[http://dx.doi.org/10.1097/JTO.0b013e31802c0276] [PMID: 17410003]
[http://dx.doi.org/10.1093/hmg/10.7.757] [PMID: 11257109]
[http://dx.doi.org/10.1186/1476-4598-3-29] [PMID: 15482598]
[http://dx.doi.org/10.1038/nature01493] [PMID: 12629553]
[http://dx.doi.org/10.1074/jbc.M611089200] [PMID: 17353198]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0416] [PMID: 15342389]
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2188] [PMID: 22142828]
[http://dx.doi.org/10.1007/s12253-015-9918-7] [PMID: 25740074]
[http://dx.doi.org/10.1038/nature07737] [PMID: 19169242]
[http://dx.doi.org/10.3390/cancers8020022] [PMID: 26891329]
[http://dx.doi.org/10.1016/j.cdip.2003.11.005]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2846] [PMID: 20530699]
[http://dx.doi.org/10.1146/annurev-cellbio-092910-154048] [PMID: 21801010]
[PMID: 22369969]
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2993] [PMID: 21189326]
[http://dx.doi.org/10.3892/ijmm.2014.1783] [PMID: 24840883]
[http://dx.doi.org/10.1158/1541-7786.MCR-12-0441] [PMID: 23525267]
[PMID: 11748155]
[http://dx.doi.org/10.1016/j.stem.2015.02.015] [PMID: 25748930]
[http://dx.doi.org/10.1186/s12943-016-0509-3] [PMID: 26988232]
[http://dx.doi.org/10.1038/nrclinonc.2010.196] [PMID: 21151206]
[http://dx.doi.org/10.1007/s00018-017-2497-x] [PMID: 28314894]
[http://dx.doi.org/10.1021/ja400034k] [PMID: 23725514]
[http://dx.doi.org/10.1016/j.ejmech.2014.11.006] [PMID: 25462278]
[http://dx.doi.org/10.1016/j.bmcl.2013.10.022] [PMID: 24176396]
[http://dx.doi.org/10.1016/j.ejmech.2016.01.018] [PMID: 26820554]
[http://dx.doi.org/10.1016/j.bmcl.2017.06.030] [PMID: 28642101]
[http://dx.doi.org/10.1021/jm500561a] [PMID: 25025991]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00310] [PMID: 26132075]
[http://dx.doi.org/10.1016/j.bmcl.2016.05.009] [PMID: 27180012]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01135] [PMID: 28122186]
[http://dx.doi.org/10.1021/acschemneuro.7b00153] [PMID: 28618224]
[http://dx.doi.org/10.1016/j.ejca.2005.06.025] [PMID: 16239105]
[http://dx.doi.org/10.1101/cshperspect.a008151] [PMID: 22570373]
[http://dx.doi.org/10.1523/JNEUROSCI.4987-09.2010] [PMID: 20203209]
[http://dx.doi.org/10.1007/s00018-009-8668-7] [PMID: 19165418]
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3054] [PMID: 16452208]
[http://dx.doi.org/10.1007/s12015-007-0023-5] [PMID: 17873349]
[http://dx.doi.org/10.1016/S1535-6108(03)00309-X] [PMID: 14706336]
[http://dx.doi.org/10.1016/j.semcancer.2004.04.015]
[http://dx.doi.org/10.1186/2045-824X-5-17] [PMID: 24066611]
[http://dx.doi.org/10.1093/carcin/bgt127] [PMID: 23585460]
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2570] [PMID: 16489059]
[http://dx.doi.org/10.1038/nrd4252] [PMID: 24781550]
[http://dx.doi.org/10.1016/j.canlet.2008.09.030] [PMID: 19022563]
[PMID: 24183943]
[http://dx.doi.org/10.1016/j.pharmthera.2013.09.005] [PMID: 24076266]
[http://dx.doi.org/10.1021/acsmedchemlett.5b00001] [PMID: 26005526]
[http://dx.doi.org/10.1016/j.bmcl.2015.03.038] [PMID: 25857941]
[http://dx.doi.org/10.1007/s10456-014-9457-y] [PMID: 25557927]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0061] [PMID: 27197169]
[http://dx.doi.org/10.1016/j.envpol.2016.08.083] [PMID: 27939630]
[http://dx.doi.org/10.1002/mc.22810] [PMID: 29566282]
[http://dx.doi.org/10.1093/annonc/mdy244] [PMID: 30060061]
[http://dx.doi.org/10.1002/mc.22873] [PMID: 29964327]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00608]
[http://dx.doi.org/10.1007/s12015-007-0004-8] [PMID: 17873377]
[http://dx.doi.org/10.3390/cells5020016]
[http://dx.doi.org/10.1016/S0027-5107(97)00150-4] [PMID: 9403032]
[http://dx.doi.org/10.1038/nrc1588] [PMID: 15803156]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01774] [PMID: 28291344]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01557] [PMID: 29870245]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00400] [PMID: 27077228]
[http://dx.doi.org/10.1016/j.ejmech.2018.06.027] [PMID: 29909338]
[http://dx.doi.org/10.1016/j.ejmech.2019.02.020] [PMID: 30771605]