Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity.
Hedgehog/smoothened signaling is active in a variety of tumors and is also involved in the maintenance of normal stem cells in vivo. We evaluated the possibility of preferential affection of tumor versus normal cells following inhibition of this signaling. We applied a cream preparation of cyclopamine (an inhibitor of the hedgehog/smoothened signaling) onto skin tumors in patients who were scheduled for the excision of these tumors (four basal cell carcinomas and a trichoepithelioma in four unrelated patients). All of the cyclopamine-treated tumors regressed rapidly. Histological and immunohistochemical analyses showed inhibition of the proliferation and highly efficient induction of the differentiation and apoptosis of tumor cells by a non-genotoxic mechanism. No adverse effects were noted and normal skin tissue and putative stem cells that were exposed to cyclopamine together with tumors were well preserved under the conditions we describe. Our findings show selective and highly efficient induction of the differentiation and apoptosis of tumor cells in vivo by transient inhibition of the hedgehog/ smoothened signaling and provide a rational cancer therapy.
Tabs
Sinan
S
Yasemin Sokak No. 6, Narlidere, Izmin 35320, Turkey. sinantas1@yahoo.com
Avci
Oktay
O
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D053823:Hedgehog Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000473:pathology* / Q000503:physiopathology; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology; D014704:Veratrum Alkaloids / Q000494:pharmacology*
D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C000541:cyclopamine