Targeting mitochondrial hexokinases increases efficacy of histone deacetylase inhibitors in solid tumor models.
Targeting mitochondrial hexokinases increases efficacy of histone deacetylase inhibitors in solid tumor models.
复制标题
DOI：
10.1016/j.yexcr.2018.12.012
复制
发表时间：
2019-02-15
影响因子：
3.7
通讯作者：
Bates SE
中科院分区：
文献类型：
--
作者：
McDonald AJ;Curt KM;Patel RP;Kozlowski H;Sackett DL;Robey RW;Gottesman MM;Bates SE
Hexokinase 1 and 2 have been shown to inhibit Bak- and Bax-mediated apoptosis, leading us to combine the histone deacetylase inhibitor romidepsin with clotrimazole or bifonazole, two compounds that reportedly decrease mitochondrial localization of hexokinases. Cancer cell lines derived from breast, kidney, lung, colon or ovarian cancers were treated with a short-term exposure to 25 ng/ml romidepsin combined with either clotrimazole or bifonazole. The combination of romidepsin with 25 μM clotrimazole or bifonazole resulted in increased annexin staining compared to cells treated with any of the drugs alone. Cell death was caspase-mediated, as the pan-caspase inhibitor Q-VD-OPh was found to inhibit apoptosis induced by the combination. A549 lung cancer cells or HCT-116 cells deficient in Bak and Bax were also resistant to apoptosis with the combination implicating the intrinsic apoptotic pathway. We found that a 24 h treatment with clotrimazole or bifonazole decreased total hexokinase 2 expression, resulting in a 76% or 60% decrease, respectively, of mitochondrial expression of hexokinase 2. Mitochondrial hexokinase 1 levels increased 2-fold or less. Our work suggests that the combination of a short-term romidepsin treatment with bifonazole or clotrimazole leads to increased apoptosis, most likely due to decreased mitochondrial expression of hexokinase 2.
登录
查看更多内容
影响因子：
6.6
作者：
Luchenko VL;Litman T;Chakraborty AR;Heffner A;Devor C;Wilkerson J;Stein W;Robey RW;Bangiolo L;Levens D;Bates SE
通讯作者：
Bates SE
影响因子：
--
作者：
Anderson M;Marayati R;Moffitt R;Yeh JJ
通讯作者：
Yeh JJ
影响因子：
16
作者：
Bhola PD;Letai A
通讯作者：
Letai A
影响因子：
3.3
作者：
Grant C;Rahman F;Piekarz R;Peer C;Frye R;Robey RW;Gardner ER;Figg WD;Bates SE
通讯作者：
Bates SE
影响因子：
4.1
作者：
Khalid, MH;Shibata, S;Hiura, T
通讯作者：
Hiura, T