title: Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells.
abstract: 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.
authors: Division of Endocrinology, Department of Medicine, St. Hedwig Hospital, Berlin, Germany.
authors: Guofang
authors: G
authors: Chen
authors: Division of Endocrinology, Department of Medicine, St. Hedwig Hospital, Berlin, Germany.
authors: Diana
authors: D
authors: Nicula
authors: Institute for Experimental Endocrinology, Charite, University Medicine, Berlin, Germany.
authors: Kostja
authors: K
authors: Renko
authors: Division of Endocrinology, Department of Medicine, St. Hedwig Hospital, Berlin, Germany.
authors: Michael
authors: M
authors: Derwahl
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000077157:Sorafenib; D018874:Spheroids, Cellular / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000473:pathology*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D004317:Doxorubicin; D008687:Metformin; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases