Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod

J Invest Dermatol. 2004 May;122(5):1266-76. doi: 10.1111/j.0022-202X.2004.22528.x.

Abstract

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Aminoquinolines / administration & dosage*
  • Aminoquinolines / pharmacology
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Biopsy
  • Cell Line, Tumor / cytology
  • Cell Line, Tumor / drug effects
  • Humans
  • Imidazoles / pharmacology
  • Imiquimod
  • Melanocytes / cytology
  • Melanocytes / drug effects
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / secondary
  • Membrane Glycoproteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Tumor Necrosis Factor / metabolism
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / metabolism
  • fas Receptor / metabolism

Substances

  • Aminoquinolines
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Imidazoles
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Imiquimod
  • resiquimod