A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells.
A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells.
复制标题
DOI：
10.3390/molecules25225407
复制
发表时间：
2020-11-19
期刊：
影响因子：
--
通讯作者：
Neidle S
中科院分区：
文献类型：
--
作者：
Ahmed AA;Neidle S
The stabilisation of G-quadruplexes (G4s) by small-molecule compounds is an effective approach for causing cell growth arrest, followed by cell death. Some of these compounds are currently being developed for the treatment of human cancers. We have previously developed a substituted naphthalene diimide G4-binding molecule (CM03) with selective potency for pancreatic cancer cells, including gemcitabine-resistant cells. We report here that CM03 and the histone deacetylase (HDAC) inhibitor SAHA (suberanilohydroxamic acid) have synergistic effects at concentrations close to and below their individual GI50 values, in both gemcitabine-sensitive and resistant pancreatic cancer cell lines. Immunoblot analysis showed elevated levels of γ-H2AX and cleaved PARP proteins upon drug combination treatment, indicating increased levels of DNA damage (double-strand break events: DSBs) and apoptosis induction, respectively. We propose that the mechanism of synergy involves SAHA relaxing condensed chromatin, resulting in higher levels of G4 formation. In turn, CM03 can stabilise a greater number of G4s, leading to the downregulation of more G4-containing genes as well as a higher incidence of DSBs due to torsional strain on DNA and chromatin structure.
登录
查看更多内容
影响因子：
14.9
作者：
Bugaut A;Balasubramanian S
通讯作者：
Balasubramanian S
影响因子：
21.8
作者：
Di Antonio M;Ponjavic A;Radzevičius A;Ranasinghe RT;Catalano M;Zhang X;Shen J;Needham LM;Lee SF;Klenerman D;Balasubramanian S
通讯作者：
Balasubramanian S
影响因子：
46.9
作者：
Lehar, Joseph;Krueger, Andrew S.;Avery, William;Heilbut, Adrian M.;Johansen, Lisa M.;Price, E. Roydon;Rickles, Richard J.;Short, Glenn F., III;Staunton, Jane E.;Jin, Xiaowei;Lee, Margaret S.;Zimmermann, Grant R.;Borisy, Alexis A.
通讯作者：
Borisy, Alexis A.
影响因子：
15
作者：
Collie, Gavin W.;Promontorio, Rossella;Parkinson, Gary N.
通讯作者：
Parkinson, Gary N.
水溶性钌 (II) 与手性 4-(2,3-二羟丙基)-甲酰胺氧代阿泊啡 (FOA) 的复合物：通过稳定 G-四链体 DNA、抑制端粒酶活性和诱导肿瘤来实现体外和体内抗癌活性
影响因子：
7.3
作者：
Chen, Zhen-Feng;Qin, Qi-Pin;Liang, Hong
通讯作者：
Liang, Hong