Photo-activation of the delocalized lipophilic cation D112 potentiates cancer selective ROS production and apoptosis.
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.
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Ning
N
Yang
Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Michael
0000-0002-8773-1425
M
Weinfeld
Faculty Saint-Jean, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Hélène
H
Lemieux
Cell Biology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Ben
0000-0002-8317-983X
B
Montpetit
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.|Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Ing Swie
IS
Goping
D017209:Apoptosis / Q000502:physiology*; D002412:Cations / Q000378:metabolism*; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D010778:Photochemotherapy / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D002412:Cations; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein