Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod.
Bypassing molecular mechanisms of apoptosis deficiency may be of great utility for the successful treatment of malignant tumors. We have discovered that imiquimod, a small-molecule immunomodulator, exerts rather tumor-selective direct pro-apoptotic activity in vivo and in vitro towards cutaneous metastases of malignant melanoma, an aggressive skin tumor. This pro-apoptotic activity was not detectable with resiquimod, a closely related structural analogue whose pro-inflammatory activity is even greater than that of imiquimod. Unresponsiveness of some melanoma metastases to imiquimod in vivo corresponded to resistance towards imiquimod-induced apoptosis in vivo and in vitro. At the molecular level, the pro-apoptotic activity of imiquimod was independent of membrane-bound death receptors, but depended on Bcl-2 expression as demonstrated by overexpression of Bcl-2 in melanoma cells. Imiquimod is the first topical compound with the potential to bypass molecular mechanisms of apoptosis deficiency, a concept that may be relevant for other tumors as well.
Schön
Michael P
MP
Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, University of Würzburg, Germany. michael.schoen@virchow.uni-wuerzburg.de
Wienrich
B Gregor
BG
Drewniok
Claudia
C
Bong
Anne B
AB
Eberle
Jürgen
J
Geilen
Christoph C
CC
Gollnick
Harald
H
Schön
Margarete
M
D000287:Administration, Topical; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001706:Biopsy; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000077271:Imiquimod; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008562:Membrane Glycoproteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D007093:Imidazoles; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000077271:Imiquimod; C402365:resiquimod