Compared to normal cells, cancer cells have a higher level of reactive oxygen species (ROS) and are under oxidative stress due to aberrant metabolism and disruption of redox homeostasis which drive their proliferation and promote progression and metastasis of cancers. Cancer cells adapt to oxidative stress by up-regulating antioxidant systems such as glutathione (GSH) to counteract the damaging effects of ROS. The altered redox balance and biological difference between normal cells and cancer cells provide a basis for the development of anticancer agents which are able to generate pharmacological ROS insults to kill cancer cells preferentially. We therefore hypothesized that elevation of oxidative stress in cancer cells by depleting glutathione or generating ROS is a logical therapeutic strategy for the development of anticancer drugs. In this work, we present novel hybrid anticancer therapeutic agents which not only weaken antioxidant defense systems but also elevate ROS production simultaneously, leading to massive ROS accumulation preferentially in cancer cells and subsequent ROS-mediated cell death. Two major components of the hybrid anticancer drugs are cinnamaldehyde and quinone methide (QM). QM is known to rapidly alkylate GSH to trigger apoptotic cell death and is therefore regarded as an antioxidant inhibitor with anticancer activity. Cinnamaldehyde is a major component of cinnamon tree and has been known to induce intracellular ROS generation, leading to apoptotic cell death. We coupled QM and cinnamaldehyde in single molecules which are able to generate QM and cinnamaldehyde in a dual stimuli triggered manner. QM and cinnamaldehyde were also expected to act in a synergistic manner to amplify oxidative stress, leading to preferential killing of cancer cells <i>in vitro</i> and <i>in vivo</i>. The hybrid anticancer drugs significantly elevated oxidative stress in cancer cells, leading to enhanced apoptotic cancer cell death through mitochondrial membrane disruption, cytochrome c release, activation of pro-caspase 3, deactivation of signal transducer and activator of transcription-3 and DNA fragmentation. The hybrid anticancer drugs also significantly suppressed the tumor growth in a mouse model of tumor xenografts without notable side effects. Oxidative stress amplifying hybrid drugs hold tremendous potential as a new anticancer drug and provide a new therapeutic paradigm which can be extended to development of hybrid anticancer drugs.

Dual stimuli-activatable oxidative stress amplifying hybrid anticancer drugs

253rd National Meeting (2017)

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