Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H 2 O 2 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 H 2 O 2 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.
A main
challenge in the development of anticancer drugs that eradicate
cancer cells specifically with minimal toxicity to normal cells is
to identify the cancer-specific properties. Cancer cells sustain a
higher level of reactive oxygen species, owing to metabolic and signaling
aberrations and unrestrained growth. Cancer cells are also furnished
with a powerful reducing environment, owing to the overproduction
of antioxidants such as glutathione (GSH). Therefore, the altered
redox balance is probably the most prevailing property of cancer cells
distinct from normal cells, which could serve as a plausible therapeutic
target. In this work, we developed a GSH-depleting pro-oxidant, benzoyloxy
dibenzyl carbonate, termed B2C, which is capable of rapidly declining
GSH and elevating oxidative stress to a threshold level above which
cancer cells cannot survive. B2C was designed to release quinone methide
(QM) that rapidly depletes GSH through esterase-mediated hydrolysis.
B2C was able to rapidly deplete GSH and induce an overwhelming level
of oxidative stress in cancer cells, leading to mitochondrial disruption,
activation of procaspase-3 and PARP-1, and cleavage of Bcl-2. In the
study of tumor xenograft models, intravenously injected B2C caused
apoptotic cell death in tumors and significantly suppressed tumor
growth. These findings provide a new insight into the design of more
effective anticancer drugs, which exploit altered redox balance in
cancer cells.
In this study, a double network hydrogel of a natural polysaccharide gellan gum (GG) hydrogel and a synthetic hydrogel poloxamer-heparin (PoH) hydrogel (PoH/GG DNH) is introduced to complement disadvantages of each hydrogel and improve the microenvironment for cell delivery. The microstructure, surface morphology, gelation temperature, swelling and weight loss, sol fraction, mechanical property and thermal stability was examined. The potential of the composite hydrogel for cell vehicle was demonstrated by encapsulation of bone marrow stem cells isolated from rabbits (rBMSCs) within the PoH/GG DNH in vitro. The results showed that the DNH system supported cell survival and retained rBMSCs morphology and phenotype. Moreover, cell distribution, adherence, and ECM production were supported by PoH/GG DNH in vivo. Overall results provide a potential opportunity to apply the composite hydrogels in tissue engineering purpose.
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