The Insulin-like Growth Factor Receptor-I (IGF-IR) Is A Potent Target For Cancer Therapy

IGF-IR is a membrane-bound tyrosine kinase receptor that plays a critical role in tumor cell proliferation, differentiation and apoptosis. The IGF-IR expression was constitutively low in normal hepatocytes and overexpressed in HCC. And what's more, the level of ligand IGF-â…¡is highly expressed in many human malignancies, including breast cancer, pediatric tumors, colon cancer and HCC. Therefore, IGF-IR is an attractive anti-tumor target for HCC.Because of high homology to insulin receptor, the development of specific small molecule inhibitors of IGF-IR tyrosine kinase activity was challengeable. Recently, many specific neutralizing antibodies for IGF-IR have been researched. Although the effects of anti-tumor about theses antibodies were tested for several cell types, no comprehensive research on the anti-tumorignic impact on HCC cells have been reported to date.Here, we generated a murine anti-IGF-IR antibody and tested our hypothesis both in vitro and in vivo by treating HCC tumor cells with the 4F2 antibody alone and in combination with the cytotoxic chemotherapeutic drugs. The anti-IGF-IR therapeutic antibody 4F2 blocks IGF-induced IGF-IR signaling and downregulates the expression of IGF-IR in HCC cells. The antitumor effect of treatment with doxorubicin could be enhanced by combining it with the 4F2.Squamous cell carcinoma of head and neck (HNSCC) is the tenth most common cancer in worldwide. In spite of advances in recent therapies, the 5-year mortality rate of SCCHN patients has not improved in the past few decades. It is important to discover novel and effective molecular-targeted approaches. Previous studies have indicated that IGF-IR is highly expressed in human head and neck cancer and that IGF-IR signaling significantly improves the proliferation, motility, and tumorigenicity of human head and neck cancer cell lines. However, the function of IGF-IR overexpression regarding therapy in human head and neck cancer is still unclear. In this study, we attempt to investigate whether IGF-IR downregulation results in an enhanced chemosensitive phenotype of head and neck cancer cells. Compared to phosphorothioate sense oligonucleotides (SS[S]ODN), IGF-IR phosphorothioate antisense oligonucleotides (AS[S]ODN) treatment inhibited cancer cell proliferation and attenuated activation of IGF-IR, IRS-1, Erk and Akt. IGF-IR antisense treatment was shown to enhance the sensitivity of SCCHN cell lines to doxorubicin in vitro and in vivo.