Abstract
Delocalized lipophilic cations (DLCs) selectively accumulate in cancer cell mitochondria and have long been explored for therapeutic applications. Although targeted effects to cancer cells are demonstrated in vitro, non-specific toxicities in vivo have hampered clinical development. Identifying the molecular mechanisms of action and enhancing selectivity are thus necessary next steps to improve these compounds and evaluate their suitability for further drug development. D112 is one such DLC with promising properties. We previously demonstrated that D112 selectively induced intrinsic apoptosis in transformed versus non-transformed cell lines. Here we show that D112 preferentially entered transformed cells where it interacted with, and damaged mitochondrial DNA, inhibited Complex I respiration and induced reactive oxygen species (ROS). ROS production was critical for Bax activation and subsequent apoptosis. Importantly, photo-activation of D112 potentiated selective ROS production and increased the window of toxicity towards cancer cells over non-transformed cells. Thus photodynamic therapy would be an exciting adjunct to D112 studies and may be generally applicable for other DLCs that are currently under therapeutic investigation.
Highlights
The small molecule D1121 belongs to a class of compounds known as delocalized lipophilic cations (DLCs)
We identified that D112 induced cell death in carcinoma-derived cell lines to a greater extent than non-transformed cell lines, accumulated in mitochondria and induced apoptosis that was dependent on BAX/BAK and inhibited by Bcl-2.1 In the current study, we investigated the mechanisms of D112-induced cellular toxicity, selective cancer cell uptake and explored strategies to enhance cancer cell specific activity
To confirm that mitochondrial respiration was required for D112-toxicity, we hypothesized that respiration-deficient mutants would be resistant
Summary
The small molecule D1121 belongs to a class of compounds known as delocalized lipophilic cations (DLCs) These compounds traverse hydrophobic plasma membranes, accumulate in mitochondria and trigger cell death.[2] Based on their mitochondria-sensing ability, DLCs have been developed for numerous applications such as imaging, targeted drug delivery and therapeutic agents. D112 is a photosensitizer that was developed by the Eastman Kodak Company for use in photographic emulsions and was subsequently found to have promising properties when assessed in a cancer drug-screening program of approximately 2000 structural dye variants.[19] We identified that D112 induced cell death in carcinoma-derived cell lines to a greater extent than non-transformed cell lines, accumulated in mitochondria and induced apoptosis that was dependent on BAX/BAK and inhibited by Bcl-2.1 In the current study, we investigated the mechanisms of D112-induced cellular toxicity, selective cancer cell uptake and explored strategies to enhance cancer cell specific activity. A combination of D112 and photodynamic therapy (PDT) could be explored for potential applications against cancer
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