Endocrine Abstracts (2006) 11 P470

Inhibition of IGF-II signal transduction improves chemosensitivity in human adrenocortical cancer cells

S Hahner, E Beidinger, A Stuermer, AC Koschker, D Weismann, M Fassnacht & B Allolio

University of Wuerzburg, Dept. of Endocrinology, Wuerzburg, Germany.

Treatment of adrenocortical carcinoma (ACC) is still unsatisfactory. As IGF-II and IGF-I receptor are frequently overexpressed in human ACC and inhibitors of the IGF system are currently under preclinical investigation, interference with IGF-signaling might have an additive effect in antitumour treatment. We have therefore analyzed several cytotoxic agents (etoposide, doxorubicine, cisplatin, streptocozin; 0.01–100 μM) on adrenal cell proliferation in vitro and further investigated, whether inhibition of IGF-II signaling or downstream inhibition of mTOR via rapamycin affects chemotherapy response in the human adrenocortical cancer cell line NCI-h295 which is known to overexpress IGF-II. IGF-signaling was inhibited by specific antibodies against IGF-I receptor or IGF-II or by the small molecule IGF-I receptor antagonist H-1356. Etoposide, doxorubicine and cisplatin inhibited cell proliferation with IC50 values of 1.2 μM, 11 μM and 9.6 μM, respectively, whereas streptocozin was inactive in NCI-h295 cells. Inhibition of IGF-signaling reduced adrenal cell proliferation and significantly increased response to the chemotherapeutic agents at cytostatic doses within therapeutic ranges (e.g. inhibition by cisplatin, etoposide or doxorubicine 10 μM alone or in combination with anti IGF-II 10 μg/ml were 61% vs 49%; 60% vs 50% or 48% vs 44% compared to controls, respectively; P<0.01). Rapamycin only slightly inhibited proliferative activity by 10.5±5% at 0.2 μM. In adrenocortical cancer cells, IGF-II appears to be a protumourigenic growth factor reducing susceptibility to apoptosis and chemotherapeutic treatment. Interference with IGF-II activity may improve response of ACC to chemotherapeutic agents. However, effects detected in NCI-h295 cells after blockade of the IGF system were clearly weaker than the effects described in other non-adrenocortical cancer cells and the clinical relevance in vivo remains to be elucidated.

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