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

Xia-Zhen Bao; Qi Wang; Xiao-Rong Ren; Fang Dai; Bo Zhou

doi:10.1016/j.freeradbiomed.2019.12.001

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

Free Radic Biol Med. 2020 May 20:152:597-608. doi: 10.1016/j.freeradbiomed.2019.12.001. Epub 2019 Dec 2.

Authors

Xia-Zhen Bao¹, Qi Wang², Xiao-Rong Ren², Fang Dai², Bo Zhou³

Affiliations

¹ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China; College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, China.
² State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China.
³ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu, 730000, China. Electronic address: bozhou@lzu.edu.cn.

PMID: 31805398
DOI: 10.1016/j.freeradbiomed.2019.12.001

Abstract

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 effects 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 (H₂O₂)-activated Cu(II) pro-ionophore strategy to develop naphthazarin (Nap) as such type of PAAs based on the H₂O₂-mediated conversion of boronate to free phenol. The boronate-protected Nap (PNap) can exploit increased levels of H₂O₂ in HepG2 cells to in situ release Nap followed by its efflux via conjugation with reduced glutathione (GSH), allowing that the Nap-GSH adduct works as a Cu(II) ionophore to induce continuously 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 H₂O₂, GSH and copper) of HepG2 cells, leading to ROS generation preferentially in HepG2 cells along with their selective death.

Keywords: Copper; Glutathione; Hydrogen peroxide; Ionophore; Reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Copper
Glutathione / metabolism
Hep G2 Cells
Hydrogen Peroxide
Ionophores
Naphthoquinones* / pharmacology
Oxidation-Reduction
Reactive Oxygen Species

Substances

Antineoplastic Agents
Ionophores
Naphthoquinones
Reactive Oxygen Species
Copper
Hydrogen Peroxide
Glutathione