A hydrogen peroxide -activated Cu(II) pro-ionophore strategy for modifying naphthazarin as a promising anticancer agent with high selectivity for generating ROS in HepG2 cells over in L02 cells
A hydrogen peroxide -activated Cu(II) pro-ionophore strategy for modifying naphthazarin as a promising anticancer agent with high selectivity for generating ROS in HepG2 cells over in L02 cells
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DOI：
10.1016/j.freeradbiomed.2019.12.001
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发表时间：
2020-05-20
影响因子：
7.4
通讯作者：
Zhou, Bo
中科院分区：
文献类型：
--
作者：
Bao, Xia-Zhen;Wang, Qi;Zhou, Bo
通过能够产生活性氧物质（ROS）的促氧化剂靶向癌细胞的氧化还原脆弱性已经作为重要的抗癌策略浮出水面。由于固有的狭窄治疗窗口和ROS产生的其他危险副作用，非常需要和具有挑战性的是开发具有高选择性的用于在癌细胞中产生ROS的促氧化抗癌剂（PAA）。在此，我们报告了一种过氧化氢（H2 O2）激活的Cu（II）亲离子载体的策略，开发萘茜素（Nap）作为这样的类型的PAA的基础上H2 O2介导的硼酸酯转化为游离苯酚。Nap（PNap）可利用HepG 2细胞内H2 O2水平的增加原位释放Nap，然后通过与还原型谷胱甘肽（GSH）结合而外排，从而使Nap-GSH加合物作为Cu（II）离子载体，通过GSH还原依赖性释放Cu（I）而持续诱导GSH耗竭。这一策略赋予PNap前所未有的能力，击中HepG 2细胞的多氧化还原特性（增加的H2 O2，GSH和铜水平），导致ROS产生优先在HepG 2细胞沿着他们的选择性死亡。
Targeting redox vulnerability of cancer cells by pro -oxidants capable of generating reactive oxygen species (ROS) has surfaced as an important anticancer strategy. Due to the intrinsic narrow therapeutic window and other dangerous side e ffects of ROS generation, it is highly needed and challenging to develop pro -oxidative anticancer agents (PAAs) with high selectivity for generating ROS in cancer cells. Herein we report a hydrogen peroxide (H 2 O 2 )-activated Cu(II) pro-ionophore strategy to develop naphthazarin (Nap) as such type of PAAs based on the H 2 O 2 -mediated conversion of boronate to free phenol. The boronate-protected Nap (PNap) can exploit increased levels of H 2 O 2 in HepG2 cells to in situ release Nap followed by its e fflux via conjugation with reduced glutathione (GSH), allowing that the Nap-GSH adduct works as a Cu(II) ionophore to induce con- tinuously GSH depletion via a reduction -dependent releasing of Cu(I) by GSH. This strategy endows PNap with the unprecedented ability to hit multi-redox characteristics (increased levels of H 2 O 2 , GSH and copper) of HepG2 cells, leading to ROS generation preferentially in HepG2 cells along with their selective death.