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.