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Breast Cancer Res Treat. 1999 Jul;56(1):1-10.

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

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1
Department of Medicine, University of Texas Health Science Center, San Antonio, USA.

Abstract

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 resistant to apoptosis-inducing chemotherapies. Therefore, we examined the effects of IGF-I on paclitaxel and doxorubicin-induced apoptosis in the IGF-I-responsive 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 next examined the effects of IGF-I and estradiol on cell survival following drug treatment in monolayer culture. IGF-I, but not estradiol, increased survival of MCF-7 cells in the presence of either drug. Cell cycle progression and counting of trypan-blue stained cells showed that IGF-I was inducing proliferation in paclitaxel-treated but not doxorubicin-treated cells. However, IGF-I decreased the fraction of apoptotic cells in doxorubicin- but not paclitaxel-treated cells. Recent work has shown that mitogen-activated protein 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-apoptotic functions while MAPK activation is associated with proliferation. We found that IGF-I rescue of doxorubicin-induced apoptosis required PI-3 kinase but not MAPK function, suggesting that IGF-I inhibited apoptosis. In contrast, IGF-I rescue of paclitaxel-induced apoptosis required both PI-3 kinase and MAPK, suggesting that IGF-I-mediated protection was due to enhancement of proliferation. Therefore, IGF-I attenuated the response of breast cancer cells to doxorubicin and paclitaxel by at least two mechanisms: induction of proliferation and inhibition of apoptosis. Thus, inhibition of IGF-I action could be a useful adjuvant to cytotoxic chemotherapy in breast cancer.

PMID:
10517338
DOI:
10.1023/a:1006208721167
[Indexed for MEDLINE]

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