Pazopanib and HDAC inhibitors interact to kill sarcoma cells
Pazopanib and HDAC inhibitors interact to kill sarcoma cells
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DOI：
10.4161/cbt.28163
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发表时间：
2014-05-01
影响因子：
3.6
通讯作者：
Dent, Paul
中科院分区：
文献类型：
--
作者：
Tavallai, Seyedmehrad;Hamed, Hossein A.;Dent, Paul
目前的研究旨在确定多激酶抑制剂帕唑帕尼是否与组蛋白脱乙酰酶抑制剂（HDACI：丙戊酸、伏立诺他）相互作用来杀死肉瘤细胞。在多种肉瘤细胞系中，在临床可达到的剂量下，帕唑帕尼和 HDACI 以相加甚至大于相加的方式相互作用，导致肿瘤细胞死亡。药物组合增加了 LC3-GFP 和 LC3-RFP 囊泡的数量。 Beclin1 或 ATG5 的敲低显着抑制了药物组合的致死率。 c-FLIP-s 的表达以及 BCL-XL 或显性失活 caspase 9 在较小程度上降低了药物组合毒性；敲除 FADD 或 CD95 具有保护作用。激活的 AKT 和激活的 MEK1 的表达是强烈抑制药物组合致死率所必需的。药物组合使 mTOR 失活，而激活的 mTOR 的表达强烈抑制药物组合的致死率。与单独使用任何一种药物相比，用帕唑帕尼和丙戊酸盐治疗携带肉瘤肿瘤的动物导致肿瘤体积的减少大于相加。由于帕唑帕尼和 HDACIs 都是 FDA 批准的药物，我们的数据支持进一步确定这种药物组合是否是临床上有用的肉瘤治疗方法。
The present studies were to determine whether the multi-kinase inhibitor pazopanib interacted with histone deacetylase inhibitors (HDACI: valproate, vorinostat) to kill sarcoma cells. In multiple sarcoma cell lines, at clinically achievable doses, pazopanib and HDACI interacted in an additive to greater than additive fashion to cause tumor cell death. The drug combination increased the numbers of LC3-GFP and LC3-RFP vesicles. Knockdown of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, and to a lesser extent BCL-XL or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 was required to strongly suppress drug combination lethality. The drug combination inactivated mTOR and expression of activated mTOR strongly suppressed drug combination lethality. Treatment of animals carrying sarcoma tumors with pazopanib and valproate resulted in a greater than additive reduction in tumor volume compared with either drug individually. As both pazopanib and HDACIs are FDA-approved agents, our data argue for further determination as to whether this drug combination is a useful sarcoma therapy in the clinic.