关键词: 甲状腺癌, 再分化治疗, MAPK抑制剂, 组蛋白去乙酰化酶抑制剂, 钠-碘转运体

Abstract: Background and purpose: Redifferentiation therapy with MAPK inhibitor is a novel strategy for radioiodine-refractory differentiated thyroid cancer, but its efficacy is relatively low. Histone deacetylase inhibitor (HDACI) is another kind of redifferetiation drug, given histone deacetylation at the sodium/iodide symporter (NIS) promoter by histone deacetylase (HDAC) as a mechanism, combined therapy using HDACI and BRAF/MEK inhibitor may produce better effect. In the present study, we assessed whether combining HDACI with BRAF/MEK inhibitor suppressing both BRAF/MEK and HDAC could more effectively induce thyroid gene expression and radioiodine uptake in thyroid cancer cells. Methods: We tested iodine and glucose handling gene expression and radioiodine uptake in BCPAP, K1, BHP 2-7 cells treated with dabrafenib/selumetinib and panobinostat alone or in combination using (real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR), Western blot, immunofluorescence, flow cytometry, radionuclide uptake/efflux assay and in vitro clonogenic assay. Results: Dabrafenib/selumetinib induced modest expression of thyroid genes and radioiodine uptake and suppressed GLUT1 expression in BCPAP and K1 cells, panobinostat showed redifferetiation effect in all the cells. Dabrafenib/selumetinib and panobinostat showed synergistic effect on redifferentiation in BCPAP and K1 cells. Conclusion: Simultaneously suppressing BRAF/MEK and HDAC induced more robust expression of thyroid genes and radioiodine uptake in thyroid cancer cells harboring BRAF^V600E compared with suppressing BRAF/MEK or HDAC alone, which warrants further investigation in animal and clinical trials.

Key words: Thyroid cancer, Redifferentiation therapy, MAPK inhibitor, Histone deacetylase inhibitor, Sodium-iodide symporter