Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

Abstract

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.

Recent advances of cocktail chemotherapy by combination drug delivery systems

“…Second, the optimal mass ratio of each chemotherapeutic within the combination drug delivery system needs to be precisely tuned, according to individual's pharmacokinetics and efficacy. The ratio of the combinatorial chemotherapeutics has been validated to play a vital role in the efficacy of combination treatment[192]. Additionally, the ratio of each individual drug holds high potential to determine the possibility of synergism and antagonism of a combination set.…”

Reactive‐Oxygen‐Species‐Responsive Drug Delivery Systems: Promises and Challenges

“…However, at high concentrations (10 μ m ) and prolonged incubation times (72 h), the prodrugs can also be activated in normal cells which are known to exhibit low levels of ROS, indicating optimal dosage and time course is critical for future applications 93. As a next step in this line of research, more recently, Lee and co‐workers have synthesized an interesting dual stimuli (ROS and pH)‐responsive prodrug that can deliver QM and ROS‐generating cinnamaldehyde (Figure 14D),94 which is a major component of cinnamon that have been widely used as food additive and considered to be safe. It has been reported that CA can induce apoptosis through ROS generation primarily in the mitochondria and inhibit growth of human cancer cells 95.…”

Activity of aminoferrocene-based prodrugs against prostate cancer

“…15 Effects of these ROS-activated prodrugs on prostate cancer have not been studied yet. Other prodrugs activated by cleavage of the B-C bond in the presence of H 2 O 2 include DNA-alkylating agents 16,17 and a recently reported cinnamaldehyde-releasing prodrug. 18 Since aggressiveness of prostate cancer has been found to correlate with the ability of the cells to produce high amounts of ROS, 3 we envisioned that aminoferrocene-based prodrugs can be potentially suitable for the treatment of prostate cancer including difficult (high-risk) cases.…”