Abstract
Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H2O2 and are also susceptible to further ROS insults. Cancer cells adapt to oxidative stress by upregulating antioxidant systems such as glutathione to counteract the damaging effects of ROS. Therefore, the elevation of oxidative stress preferentially in cancer cells by depleting glutathione or generating ROS is a logical therapeutic strategy for the development of anticancer drugs. Here we report a dual stimuli-responsive hybrid anticancer drug QCA, which can be activated by H2O2 and acidic pH to release glutathione-scavenging quinone methide and ROS-generating cinnamaldehyde, respectively, in cancer cells. Quinone methide and cinnamaldehyde act in a synergistic manner to amplify oxidative stress, leading to preferential killing of cancer cells in vitro and in vivo. We therefore anticipate that QCA has promising potential as an anticancer therapeutic agent.
Highlights
Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H2O2 and are susceptible to further ROS insults
We developed QCA, [4-(1,3, 2-dioxaborinan-2-yl)benzyl ((5-methyl-2-styryl-1,3-dioxan-5-yl) methyl) carbonate] as a novel hybrid anticancer prodrug by coupling a quinone methide (QM)-generating moiety to ROS-generating cinnamaldehyde, which is capable of amplifying oxidative stress in cancer cells to induce enhanced apoptotic cell death
The acetal protons appeared at B5.1 p.p.m. and the methylene protons next to boronic ester appeared at B4.1 p.p.m., demonstrating the successful coupling of H2O2-responsive boronate to cinnamaldehyde via a carbonate linker
Summary
Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H2O2 and are susceptible to further ROS insults. There have been increasing efforts to develop a strategy to increase the level of ROS in cancer cells leading to ROS-mediated cancer cell death, which is named as ‘oxidation therapy’[1,12,14] One way of this anticancer therapy is to deliver ROS-generating agents to tumour tissues directly, such as arsenic trioxide (As2O3) and glucose oxidase[17]. Another approach of oxidation therapy is to disrupt the redox balance in cancer cells by suppressing the antioxidant systems. Manipulating the ROS levels by redox modulation is a logical approach to selectively kill cancer cells without causing significant toxicity to normal cells and would have broad therapeutic applications for cancer treatment
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