The type-I insulin like growth factor (IGF-IR) is either activated and/or overexpressed in a wide range of tumor types and contributes to tumorigenicity, proliferation, survival, metastasis and drug resistance. Disruption of IGF-IR signaling alone or in combination with other cytotoxic agents has emerged as an important strategy in cancer therapy. Our laboratory has shown that sequentially combining doxorubicin with anti-IGF-IR antibodies significantly enhances the response of chemotherapy, while the opposite sequence causes cells resistant to chemotherapy. Here, we show that a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF-IR and insulin receptor (IR) kinase activity and proliferation in MCF-7 and MDA435/LCC6 cell lines. Moreover, PQIP treatment blocked both IGF-I and insulin stimulated activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in both cell lines. At doses that inhibited monolayer cell growth, the compound also inhibited cell motility, blocked IGF-I stimulated S-phase progression and induced autophage; at higher doses, it also caused PARP cleavage. Combining PQIP with doxorubicin significantly enhanced cytotoxicity but did not further enhance doxorubicin-induced PARP cleavage in monolayer cell growth. Furthermore, our sequencing studies showed that combining PQIP with doxorubicin simultaneously or doxorubicin followed by PQIP significantly inhibited the anchorage-independent growth in both MCF-7 and MDA435/LCC6 cells. In contrast, pre-treatment with PQIP followed by doxorubicin did not enhance the cytotoxicity of doxorubicin in anchorage-independent growth, which is similar as anti-IGF-IR antibodies in combination with doxorubicin. In summary, these results suggest that the IGF-IR tyrosine kinase inhibitor PQIP can be used alone or in combination with chemotherapy to enhance cytotoxicity of human tumor cell lines, and the timing of IGF-IR inhibition may affect responses to doxorubicin.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6110.