Targeting endothelin receptor type A in human cervical carcinoma cells.
Human papilloma viruses are associated with cervical cancer and enhance signal transduction of growth factors. In human papilloma virus-positive cervical cancer cells, the endothelin-A receptor mediates the endothelin-1-induced mitogenic effect, and sustains the basal growth rate of unstimulated cervical tumor cells. In this study, the action of a specific endothelin-A receptor antagonist (atrasentan) and a truly 'balanced' endothelin-A/endothelin-B antagonist (A-182086), was analysed in the human cervical carcinoma cells, CaSki and C33A. CaSki cells are human papilloma virus-16-positive, produce endothelin-1 and possess endothelin-A and endothelin-B receptors, whereas the C33A line is human papilloma virus-negative, does not secrete endothelin-1 and has only endothelin-B receptors. In human papilloma virus-positive cancer cells both antagonists caused a similar drastic reduction in BrdU incorporation and in the growth rate. These data clearly demonstrate that A-182086 and atrasentan show similar potency and also indicate that blocking of the endothelin-B receptor by A- 182086 does not increase the anti-proliferative effect. This finding suggests that the endothelin-B receptor does not participate in the growth control of CaSki cells. Results from C33A cells reinforce this previous conclusion as both compounds are ineffective in altering the BrdU uptake of these cells in basal and endothelin-1 stimulated conditions. In conclusion, targeting the endothelin-A receptor, but not the endothelin-B receptor, may be a valid tool in the therapy of cervical carcinoma.
Cirilli
Alessia
A
Laboratory of Virology, Regina Elena Cancer Institute, Rome, Italy.
Simeone
Paola
P
Muller
Antonio
A
Bagnato
Anna
A
Venuti
Aldo
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077868:Atrasentan; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D052162:Human papillomavirus 16 / Q000302:isolation & purification; D006801:Humans; D011759:Pyrrolidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology
C467893:A 182086; D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D000077868:Atrasentan