Proliferative thyroid diseases are more prevalent in females than in males. Upon the onset of puberty, the incidence of thyroid cancer increases in females only and declines again after menopause. Estrogen is a potent growth factor both for benign and malignant thyroid cells that may explain the sex difference in the prevalence of thyroid nodules and thyroid cancer. It exerts its growth-promoting effect through a classical genomic and a non-genomic pathway, mediated via a membrane-bound estrogen receptor. This receptor is linked to the tyrosine kinase signaling pathways MAPK and PI3K. In papillary thyroid carcinomas, these pathways may be activated either by a chromosomal rearrangement of the tyrosine receptor kinase TRKA, by RET/PTC genes, or by a BRAF mutation and, in addition, in females they may be stimulated by high levels of estrogen. Furthermore, estrogen is involved in the regulation of angiogenesis and metastasis that are critical for the outcome of thyroid cancer. In contrast to other carcinomas, however, detailed knowledge on this regulation is still missing for thyroid cancer.

Sorafenib, a multikinase inhibitor has recently been approved for the treatment of radio-iodine refractory thyroid carcinoma. However, toxic side effects may lead to dose reduction. In the present study, we analyzed whether a combined therapy with metformin may allow a dose reduction of sorafenib without loss of effectiveness at the same time. In HTh74 anaplastic thyroid carcinoma (ATC) cells and its derived doxorubicin-resistant HTh74Rdox cell line, the growth inhibitory effect of sorafenib with or without metformin was investigated. Furthermore, an analysis of cell cycle arrest in response to sorafenib was performed and the ability of a combined treatment to induce apoptosis was analyzed. In addition, the effects on clonal growth and formation of stem cell-derived spheres were assayed. The influence of sorafenib and metformin on MAP kinase pathway was investigated by analysis of ERK phosphorylation. Sorafenib and metformin synergistically inhibited growth of the two thyroid cancer cell lines, with a more pronounced effect on the doxorubicin-resistant HTh74Rdox cell line. The two drugs also synergistically decreased sphere formation, which suggested a specific effect on thyroid cancer stem cells. The addition of metformin enabled a 25% dose reduction of sorafenib without loss of its growth inhibitory efficacy. Sorafenib and metformin synergistically decreased the proliferation of ATC cell lines and the outgrowth of their derived cancer stem cells. A combined treatment enabled a significant dose reduction of sorafenib. In respect to frequent toxic side effects, clinical studies in future should demonstrate whether the addition of metformin may be an advantage in the chemotherapy of patients with radio-iodine‑resistant thyroid cancer.

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