期刊
CELLS
卷 9, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/cells9071661
关键词
glioblastoma; gamitrinib; HDAC inhibitors; tumor metabolism; electron transport chain; Bcl-2 family
类别
资金
- NIH NINDS [R01NS095848, R01NS102366, K08NS083732]
- Louis V. Gerstner, Jr. Scholars Program (2017-2020)
- American Brain Tumor Association Discovery Grant 2017 [DG1700013]
- American Brain Tumor Association Basic Research Fellowship in Memory of Katie Monson [BRF1900018]
- Cancer Center Flow Core Facility [P30CA013696, S10RR027050]
The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据