The combination of the glycolysis inhibitor 2-DG and sorafenib can be effective against sorafenib-tolerant persister cancer cells
The combination of the glycolysis inhibitor 2-DG and sorafenib can be effective against sorafenib-tolerant persister cancer cells
复制标题
糖酵解抑制剂 2-DG 和索拉非尼的组合可有效对抗索拉非尼耐受的持久性癌细胞。
DOI：
10.2147/ott.s212465
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Liu, Xiaoxia
中科院分区：
文献类型：
--
作者：
Li Wang;Yang, Qian;Liu, Xiaoxia
背景资料：化疗仍然是通过消除快速增长的癌细胞群体来成功治疗癌症的主要临床选择。然而，耐药性导致抗肿瘤治疗的失败。越来越多的证据表明，一小部分癌细胞亚群在药物压力下会进入“持续状态”。持续存在的细胞库构成了耐药性可能出现的储存库。因此，靶向持续存在的细胞提出了一个治疗的机会，以防止耐药性和阻碍肿瘤revolution.Materials和方法：RT-qPCR，Western blot，海马，细胞凋亡测定，克隆形成测定，和异种移植小鼠model.Results：我们发现，一个类似的治疗耐药细胞状态的基础上的行为来自索拉非尼治疗可逆的，非突变机制。然后，我们证明了持久细胞显示出上调的糖酵解，如更高的ECAR所证明的，以及增加的葡萄糖消耗和乳酸盐产生。数据库分析显示，索拉非尼耐受的持续细胞表现出糖酵解酶己糖激酶2的表达增加，这与肝癌的不良预后密切相关。我们发现，糖酵解抑制剂2-DG和索拉非尼的联合处理增加了持久细胞凋亡，抑制了集落形成。因此，我们证明，当persister细胞暴露于低浓度的索拉非尼时，它们遭受线粒体功能障碍，但显示出糖酵解的代偿性增加，这有助于细胞生长和增殖。最后，我们发现，2-DG和索拉非尼的组合减少持续性肿瘤生长在mice.Conclusions：这些研究结果表明，这样的组合可以有效地阻碍持续性细胞的生长，并可能代表一个有前途的治疗策略，以防止持续性细胞耐药。
Background: Chemotherapy remains a major clinical option for the successful treatment of cancer by eliminating fast-growing populations of cancer cells. However, drug resistance causes the failure of antitumor treatment. Increasing evidence suggests that a small subpopulation of cancer cells will enter a "persister state" under drug pressure. The persister cell pool constitutes a reservoir from which drug resistance may emerge. Therefore, targeting persister cells presents a therapeutic opportunity to prevent drug resistance and impede tumor relapse.Materials and methods: RT-qPCR, Western blot, Seahorse, apoptosis assay, clonogenic assay, and xenografted mouse model were used for this study.Results: We showed that a similar therapy-resistant cell state underlies the behavior of persister cells derived from sorafenib treatments with reversible, nonmutational mechanisms. Then, we demonstrated that persister cells showed upregulated glycolysis, as evidenced by higher ECAR, as well as increased glucose consumption and lactate production. A database analysis showed that sorafenib-tolerant persister cells exhibited the increased expression of the glycolytic enzyme hexokinase 2, which is closely related to the poor prognosis in liver cancer. We found that the combined treatment with the glycolytic inhibitor 2-DG and sorafenib increased persister cell apoptosis and inhibited colony formation. Consequently, we demonstrated that when persister cells were exposed to a low concentration of sorafenib, they suffered mitochondrial dysfunction but showed compensatory increases in glycolysis, which contributes to cell growth and proliferation. Finally, we showed that the combination of 2-DG and sorafenib reduced persister tumor growth in mice.Conclusions: These findings suggest that such a combination can effectively hamper persister cell growth and may represent a promising therapeutic strategy to prevent persister cell resistance.