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This explains the tumour's extraordinary resistance to the standard treatment. Imiquimod is a topical immune response modifier (imidazoquinoline) with both antiviral and antitumour activities. The mechanism by which imiquimod triggers the apoptosis of melanoma cells has now been carefully elucidated. Imiquimod\u2010induced apoptosis is associated with the activation of apoptosis signalling regulating kinase1\/c\u2010Jun\u2010N\u2010terminal kinase\/p38 pathways and the induction of endoplasmic stress characterized by the activation of the protein kinase <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010like endoplasmic reticulum kinase signalling pathway, increase in intracellular Ca<jats:sup>2+<\/jats:sup> release, degradation of calpain and subsequent cleavage of caspase\u20104. Moreover, imiquimod triggers the activation of <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010\u03baB and the expression of the inhibitor of apoptosis proteins (<jats:styled-content style=\"fixed-case\">IAP<\/jats:styled-content>s) such as, X\u2010linked <jats:styled-content style=\"fixed-case\">IAP<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">XIAP<\/jats:styled-content>) together with the accumulation of reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>). Also, imiquimod triggers mitochondrial dysregulation characterized by the loss of mitochondrial membrane potential (\u0394\u03c8m), the increase in cytochrome c release, and cleavage of caspase\u20109, caspase\u20103 and poly(ADP\u2010ribose) polymerase (PARP). Inhibitors of specific pathways, permit the elucidation of possible mechanisms of imiquimod\u2010induced apoptosis. They demonstrate that inhibition of NF\u2010kB by the inhibitor of nuclear factor kappa\u2010B kinase (IKK) inhibitor Bay 11\u2010782 or knockdown of XIAP induces melanoma apoptosis in cells exposed to imiquimod. These findings support the use of either IKK inhibitors or IAP antagonists as adjuvant therapies to improve the effectiveness topical imiquimod in the treatment of melanoma.<\/jats:p>","DOI":"10.1111\/jcmm.12718","type":"journal-article","created":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T10:52:48Z","timestamp":1447843968000},"page":"266-286","source":"Crossref","is-referenced-by-count":35,"title":["Imiquimod\u2010induced apoptosis of melanoma cells is mediated by <scp>ER<\/scp> stress\u2010dependent Noxa induction and enhanced by <scp>NF<\/scp>\u2010\u03baB inhibition"],"prefix":"10.1111","volume":"20","author":[{"given":"Abdelouahid","family":"El\u2010Khattouti","sequence":"first","affiliation":[{"name":"Cancer Institute University of Mississippi Medical Center Jackson MS USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Selimovic","sequence":"additional","affiliation":[{"name":"Clinic of Operative Dentistry, Periodontology and 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