Combination therapy with histone deacetylase inhibitors and lithium chloride: a novel treatment for carcinoid tumors.
Combination therapy with histone deacetylase inhibitors and lithium chloride: a novel treatment for carcinoid tumors.
复制标题
DOI：
10.1245/s10434-008-0194-6
复制
发表时间：
2009-02
影响因子：
3.7
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
在类癌细胞系中，组蛋白脱乙酰酶抑制剂丙戊酸和琥珀酰基双异羟肟酸激活Notch1途径，而锂抑制糖原合成酶β(GSK-3β)。这些化合物在体外会限制生长并减少激素的分泌。我们假设，低剂量的HDAC抑制剂和氯化锂联合治疗可以达到与单独药物类似的生长抑制作用。用VPA或SBHA和氯化锂处理胃肠道和肺类癌细胞48h。免疫印迹法检测对Notch1、GSK-3β通路及神经内分泌肿瘤标志物嗜铬粒蛋白A(CgA)的影响。细胞增殖实验测定细胞生长情况。在小剂量联合治疗中，观察到CGA降低。HDAC抑制剂增加了Notch1蛋白的活性，而锂处理与抑制GSK-3β有关。此外，低剂量联合治疗可抑制肿瘤细胞的生长。用丙戊酸或苯丙氨酸和氯化锂处理类癌细胞可抑制神经内分泌标记物CgA，同时上调Notch1和抑制GSK-3β。这种组合有效地抑制了增长。因此，低剂量联合治疗可能是一种可行的类癌治疗方法。在类癌细胞系中，Notch1通路的激活和糖原合成酶激酶-3β的抑制限制了体外生长和激素分泌。同时针对这些途径的低剂量联合治疗有效地抑制了生长和限制了激素的分泌。因此，低剂量联合治疗可能是一种可行的类癌治疗方法。
In carcinoid cell lines, the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 pathway, while lithium inhibits glycogen synthase kinase-3β (GSK-3β). These compounds limit growth and decrease hormonal secretion in vitro. We hypothesized that lower-dose combination therapy of HDAC inhibitors and lithium chloride could achieve similar growth inhibition to that of the drugs alone. GI and pulmonary carcinoid cells were treated with either VPA or SBHA and lithium chloride for up to 48 hours. Western analysis was used to measure the effects on the Notch1 and GSK-3β pathways and the neuroendocrine tumor marker chromogranin A (CgA). Growth was measured by a cellular proliferation assay. With lower-dose combination therapy, a decrease in CgA was observed. The HDAC inhibitors increased the amount of active Notch1 protein, while treatment with lithium was associated with inhibition of GSK-3β. Moreover, growth was inhibited with lower-dose combination therapy. Treatment of carcinoid cells with either VPA or SBHA and lithium chloride suppresses the neuroendocrine marker CgA while upregulating Notch1 and inhibiting GSK-3β. This combination effectively reduces growth. Thus, lower-dose combination therapy may be a viable therapeutic approach for carcinoid tumors. In carcinoid cell lines, activate of the Notch1 pathway and inhibition of the glycogen synthase kinase-3β limit growth and decrease hormonal secretion in vitro. Lower-dose combination therapy to simultaneously target these pathways effectively reduced growth and limited hormonal secretion. Thus, lower-dose combination therapy may be a viable therapeutic approach for carcinoid tumors.
登录
查看更多内容
影响因子：
9
作者：
Greenblatt, David Yu;Cayo, Max A.;Chen, Herbert
通讯作者：
Chen, Herbert
影响因子：
5.8
作者：
Kunnimalaiyaan, Muthusamy;Chen, Herbert
通讯作者：
Chen, Herbert
影响因子：
6.2
作者：
Modlin, IM;Lye, KD;Kidd, M
通讯作者：
Kidd, M
影响因子：
2.2
作者：
Platta, Christopher S.;Greenblatt, David Yue;Chen, Herbert
通讯作者：
Chen, Herbert
影响因子：
3.8
作者：
Kappes, Ashley;Vaccaro, Abram;Chen, Herbert
通讯作者：
Chen, Herbert