PMID- 12902443
OWN - NLM
STAT- MEDLINE
DCOM- 20030813
LR  - 20190513
IS  - 1460-2105 (Electronic)
IS  - 0027-8874 (Linking)
VI  - 95
IP  - 15
DP  - 2003 Aug 6
TI  - Tumor-selective induction of apoptosis and the small-molecule immune response 
      modifier imiquimod.
PG  - 1138-49
AB  - BACKGROUND: The incidence of nonmelanoma skin cancer, basal cell carcinomas 
      (BCCs), and squamous cell carcinomas (SCCs) is increasing, representing a major 
      medical and economic problem. Imiquimod, a topical small-molecule immune response 
      modifier, has shown efficacy toward BCC and actinic keratoses in clinical trials. 
      Imiquimod acts both indirectly, via cytokine-mediated stimulation of cellular 
      immune responses, and directly, through unknown mechanisms against tumor cells. 
      We examined the mechanism by which imiquimod induces apoptosis in cancer cells. 
      METHODS: Apoptosis was assessed by enzyme-linked immunosorbent assay, western 
      blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick end 
      labeling (TUNEL) assays in five SCC cell lines, HaCaT cells (a spontaneously 
      immortalized human keratinocyte cell line), and normal keratinocytes treated with 
      imiquimod, with its analog resiquimod, or with neither. Expression of death 
      receptors, caspases, and cytochrome c in the apoptotic signaling cascade was 
      analyzed using western blot and flow cytometric analyses. The functional 
      relevance of imiquimod-induced cytochrome c release was assessed by transfection 
      of HaCaT cells with Bcl-2. Apoptosis in BCCs in vivo was assessed by TUNEL assays 
      of imiquimod-treated and untreated tumors from three patients. Differences 
      between treated and untreated cells and tumors were determined using a two-tailed 
      Student's t test. RESULTS: Imiquimod, but not resiquimod, induced apoptosis in 
      all SCC cell lines and HaCaT cells. This induction involved activation of several 
      caspases and Bcl-2-dependent cytosolic translocation of cytochrome c but was 
      independent of the membrane-bound death receptors Fas, tumor necrosis 
      factor-related apoptosis-inducing ligand (TRAIL)-R1-R4 receptors, and tumor 
      necrosis factor-R1 and -R2 receptors. Topical application of imiquimod to BCC 
      tumors in vivo induced apoptosis. CONCLUSION: Imiquimod has the potential to 
      induce apoptosis in skin cancer cells, possibly by circumventing mechanisms 
      developed by malignant tumors to resist apoptotic signals.
FAU - Schon, Margarete
AU  - Schon M
AD  - Department of Dermatology, Otto-von-Guericke-University, Magdeburg, Germany. 
      schoenmargret@web.de
FAU - Bong, Anne B
AU  - Bong AB
FAU - Drewniok, Claudia
AU  - Drewniok C
FAU - Herz, Jeannine
AU  - Herz J
FAU - Geilen, Christoph C
AU  - Geilen CC
FAU - Reifenberger, Julia
AU  - Reifenberger J
FAU - Benninghoff, Bernd
AU  - Benninghoff B
FAU - Slade, Herbert B
AU  - Slade HB
FAU - Gollnick, Harald
AU  - Gollnick H
FAU - Schon, Michael P
AU  - Schon MP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Aminoquinolines)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cytochrome c Group)
RN  - 0 (Imidazoles)
RN  - 0 (Immunologic Factors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - P1QW714R7M (Imiquimod)
RN  - V3DMU7PVXF (resiquimod)
SB  - IM
MH  - Aminoquinolines/*pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects/*immunology
MH  - Blotting, Western
MH  - Carcinoma, Basal Cell/drug therapy/immunology
MH  - Carcinoma, Squamous Cell/*drug therapy/*immunology/metabolism
MH  - Caspase 3
MH  - Caspases/drug effects
MH  - Cytochrome c Group/drug effects
MH  - DNA Fragmentation/drug effects
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Imiquimod
MH  - Immunologic Factors/*pharmacology
MH  - In Situ Nick-End Labeling
MH  - Keratinocytes/drug effects/immunology
MH  - Proto-Oncogene Proteins c-bcl-2/drug effects
MH  - Receptors, Tumor Necrosis Factor/drug effects
MH  - Tumor Cells, Cultured
MH  - Up-Regulation/drug effects
EDAT- 2003/08/07 05:00
MHDA- 2003/08/14 05:00
CRDT- 2003/08/07 05:00
PHST- 2003/08/07 05:00 [pubmed]
PHST- 2003/08/14 05:00 [medline]
PHST- 2003/08/07 05:00 [entrez]
AID - 10.1093/jnci/djg016 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 2003 Aug 6;95(15):1138-49. doi: 10.1093/jnci/djg016.