Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Int J Mol Sci. 2018 Jun 22;19(7):1834. doi: 10.3390/ijms19071834.
Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPARγ), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21 and p27, and the reduction of hyperphosphorylated retinoblastoma protein (pp-Rb)-E2F1 signaling. Therefore, targeting two pathways involved in lipid metabolism may provide a new direction for treating ATC.
间变性甲状腺癌（ATC）是甲状腺癌的一种恶性亚型，其发病机制尚不清楚。重要的是，由于 ATC 对常规治疗（包括放射性碘治疗和促甲状腺激素抑制）无反应，因此尚无有效的治疗策略。在这里，我们报告了一种联合用药方法，该方法由针对脂质代谢的药物组成，包括洛伐他汀（3-羟基-3-甲基戊二酰基辅酶 A 还原酶抑制剂，HMGCR）和曲格列酮（过氧化物酶体增殖物激活受体γ激动剂，PPARγ），在细胞培养系统中表现出抗增殖作用，并在小鼠异种移植模型中导致肿瘤消退。该组合物包含两种药物的亚致死浓度，并且对某些类型的正常细胞表现出低毒性。我们的结果支持了一种假说，即该组合的抑制作用部分是通过细胞周期停滞在 G0/G1 期实现的，这可通过诱导细胞周期蛋白依赖性激酶抑制剂 p21 和 p27 以及降低高磷酸化视网膜母细胞瘤蛋白（pp-Rb）-E2F1 信号来证明。因此，靶向涉及脂质代谢的两条途径可能为治疗 ATC 提供新的方向。
