Evidence of increased apoptosis and reduced proliferation in basal cell carcinomas treated with tazarotene.
A preliminary clinical experience suggested tazarotene, a new acetylenic retinoid, as an effective alternative topical treatment of basal cell carcinomas (BCC). The mechanisms of action of this synthetic retinoid, however, have not been yet clarified. In this work we assessed the in vivo effects of daily application of tazarotene for 24 wk, on 30 small superficial and nodular BCC, and the in vitro effects of tazarotene on immortalized basal and squamous tumor epidermal cells. Cellular proliferation, apoptosis and changes in expression of retinol and retinoic acid receptors (RAR), p53, bcl-2, and bax were studied by immunohistochemistry, western blotting and PCR. Overall, 76.7% of treated tumors showed >50% regression. Complete healing was observed in 46.7% of all treated BCC, without recurrences at 2-y observation. Regression was associated with reduced proliferation and increased apoptosis, demonstrated by Ki-67- and TdT-mediated dUTP-biotin nick-end labelling-positive nuclear staining, and with enhanced RAR-beta and bax expression, with RAR-alpha and -gamma expression unchanged. In vitro, tazarotene induced a concentration-dependent increase of RAR-beta and bax associated with a greater rate of apoptosis and growth inhibition in basaloid tumor cells compared with squamous tumor cells. Our studies provide convincing evidence that tazarotene induces BCC regression possibly by synergistic RAR-beta-dependent anti-proliferative and pro-apoptotic pathways.
Orlandi
Augusto
A
Department of Biopathology and Image Diagnostics, Anatomic Pathology Institute, University of Rome, Italy. orlandi@uniroma2.it
Bianchi
Luca
L
Costanzo
Antonio
A
Campione
Elena
E
Giusto Spagnoli
Luigi
L
Chimenti
Sergio
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D006801:Humans; D008875:Middle Aged; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein; D012176:Retinoids
D003879:Dermatologic Agents; D009539:Nicotinic Acids; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C082925:retinoic acid receptor beta; C086827:tazarotene; D012176:Retinoids