Inhibition of growth in medullary thyroid cancer cells with histone deacetylase inhibitors and lithium chloride.
Inhibition of growth in medullary thyroid cancer cells with histone deacetylase inhibitors and lithium chloride.
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DOI：
10.1016/j.jss.2008.08.004
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Adler JT;Hottinger DG;Kunnimalaiyaan M;Chen H
虽然仅占甲状腺恶性肿瘤的3%，但甲状腺髓样癌（MTC）占甲状腺癌死亡的14%。MTC复发率高，缺乏有效治疗。组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VPA）和辛二酰双异羟肟酸（SBHA）激活Notch 1信号通路，而氯化锂抑制糖原合成酶激酶-3（GSK-3）通路。这些化合物已被证明可以限制生长并抑制激素分泌;因此，针对不同的信号通路可能是一种有效的治疗方法。用高达20 mM氯化锂与3 mM VPA或20 μM SBHA的不同组合处理MTC细胞48小时。Western分析用于测量对Notch 1、GSK-3 β和神经内分泌（NE）标志物的影响。通过溴化甲基噻唑基二苯基四唑（MTT）细胞增殖试验评估生长。Western分析用于确定生长调节的机制。联合治疗增加了Notch 1的活性，抑制了GSK-3 β通路，并降低了NE标志物。在联合治疗中观察到生长的叠加抑制。较低剂量的联合治疗实现了更大的NE标志物和增长的下降比任何单独的药物治疗。此外，还观察到凋亡标志物caspase-3和PARP的裂解增加。氯化锂和HDAC抑制剂的联合治疗通过体外MTC细胞的凋亡抑制NE标志物并降低生长。随着疗效的提高和毒性的降低，联合治疗可能代表治疗MTC的新策略。
While representing only 3% of thyroid malignancies, medullary thyroid cancer (MTC) accounts for 14% of thyroid cancer deaths. MTC has a high rate of recurrence and lacks effective treatments. The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 signaling pathway, while lithium chloride inhibits the glycogen synthase kinase-3ß (GSK-3ß) pathway. These compounds have been shown to limit growth and suppress hormonal secretion; thus, targeting different signaling pathways may be an effective treatment. MTC cells were treated with varying combinations of up to 20 mM lithium chloride with either 3 mM VPA or 20 μM SBHA for 48 hours. Western analysis was used to measure the effects on Notch1, GSK-3ß, and neuroendocrine (NE) markers. Growth was assessed by a methylthiazolyldiphenyl-tetrazolium (MTT) bromide cellular proliferation assay. Western analysis was used to determine the mechanism of growth regulation Combination therapy increased active Notch1, inhibited the GSK-3ß pathway, and decreased NE markers,. Additive inhibition of growth was observed with combination therapy. Lower-dose combination therapy achieved greater decreases on NE markers and growth than treatment with any of the drugs alone. Moreover, an increase in the cleavage of the apoptotic markers caspase-3 and PARP was observed. Combination therapy with lithium chloride and HDAC inhibitors suppresses NE markers and decreases growth via apoptosis of MTC cells in vitro. With the possibility of increased efficacy and decreased toxicity, combination therapy may represent a new strategy to treat MTC.
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