Effect of Perioperative Treatment with a Hypoxia-inducible Factor-1-alpha Inhibitor in an Orthotopic Surgical Mouse Model of Thyroid Cancer

Abstract

Despite an excellent prognosis, some patients with thyroid cancer suffer from locally invasive disease that cannot be controlled by conventional therapy. Our previous study suggested that hypoxia inducible factor-1-alpha (HIF1α) might be an important marker for the identification of and a target for treatment of intractable thyroid cancer. Therefore, in the present study, we established an orthotopic mouse surgical model of thyroid cancer that mimics the clinical setting, and evaluated the effect of perioperative adjuvant treatment with a HIF1α inhibitor. Seven thyroid cancer cell lines (SNU-790, BCPAP, KTC1, TPC1, TPC1-M, KTC2, and FRO) and four HIF1α inhibitors (echinomycin, LAQ824, temsirolimus, and vorinostat) were used in this study. Expression of HIF1α and related proteins was evaluated in the cell lines

immunoblotting and cell proliferation assays were conducted

and echinomycin was validated in an orthotopic surgical mouse model. Nuclear expression of HIF1α increased in the tumorigenic cell lines. HIF1α inhibitors inhibited proliferation and colony formation in all the cell lines. In the orthotopic surgical model, the group treated with surgery and echinomycin treatment group showed a highly significant survival gain (p=0.001) compared to the control group. The highly significant survival gain resulting from their use in perioperative adjuvant treatment in vivo and their anticancer effect in vitro suggest that HIF1α inhibitors might be candidate as perioperative adjuvant chemotherapeutic agents for thyroid cancer. Combining adjuvant HIF1α inhibitor chemotherapy with surgery might be an effective therapeutic strategy for thyroid cancer that is refractory to conventional treatments.