Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death - proliferative and anti-apoptotic effects

Insulin-like growth factor (IGF)-I protects many cell types from apoptosis. As a result, it is possible that IGF-I-responsive cancer cells may be resi stant to apoptosis-inducing chemotherapies. Therefore, we examined the effe cts of IGF-I on paclitaxel and doxorubicin-induced apoptosis in the IGF-I-r esponsive breast cancer cell line MCF-7. Both drugs caused DNA laddering in a dose-dependent fashion, and IGF-I reduced the formation of ladders. We n ext examined the effects of IGF-I and estradiol on cell survival following drug treatment in monolayer culture. IGF-I, but not estradiol, increased su rvival of MCF-7 cells in the presence of either drug. Cell cycle progressio n and counting of trypan-blue stained cells showed that IGF-I was inducing proliferation in paclitaxel-treated but not doxorubicin-treated cells. Howe ver, IGF-I decreased the fraction of apoptotic cells in doxorubicin- but no t paclitaxel-treated cells. Recent work has shown that mitogen-activated pr otein kinase (MAPK) and phosphotidylinositol-3 (PI-3) kinase are activated by IGF-I in these cells. PI-3 kinase activation has been linked to anti-apo ptotic functions while MAPK activation is associated with proliferation. We found that IGF-I rescue of doxorubicin-induced apoptosis required PI-3 kin ase but not MAPK function, suggesting that IGF-I inhibited apoptosis. In co ntrast, IGF-I rescue of paclitaxel-induced apoptosis required both PI-3 kin ase and MAPK, suggesting that IGF-I-mediated protection was due to enhancem ent of proliferation. Therefore, IGF-I attenuated the response of breast ca ncer cells to doxorubicin and paclitaxel by at least two mechanisms: induct ion of proliferation and inhibition of apoptosis. Thus, inhibition of IGF-I action could be a useful adjuvant to cytotoxic chemotherapy in breast canc er.