Synthetic retinoid CD437 promotes rapid apoptosis in malignant human epidermal keratinocytes and G1 arrest in their normal counterparts.
Four human cutaneous squamous cell carcinoma (SCC) cell lines and normal human epidermal keratinocyte (NHEK) cells from two donors were examined for sensitivity to the synthetic retinoid 6-[3-(1 -adamantyl)-4-hydroxyphenyl]-2-naph-thalene carboxylic acid (CD437) alone or in combination with other agents. CD437 promoted rapid (within 2 h) apoptosis in SCC cells and G1 arrest in NHEK cells. G1 arrest in NHEK cells was sustained for 48 h while apoptosis occurred in approximately 60% of SCC cell after 24 h. Apoptosis could not be inhibited by nuclear retinoic acid receptor antagonists or cycloheximide, indicating CD437 was functioning in a receptor-independent manner. All-trans retinoic acid not only failed to induce apoptosis in SCC cells even at 20-fold higher concentration relative to the effective concentration of CD437; it also decreased the efficacy of CD437. Because of its differential effects on normal versus malignant keratinocytes, CD437 may be useful for the prevention or treatment of cutaneous SCC.
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Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4095, USA.
Lotan
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D053938:DNA Fragmentation; D004817:Epidermis / Q000473:pathology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D012176:Retinoids / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; C099555:CD 437; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D012176:Retinoids; D014212:Tretinoin