Insights into the mechanism of safingol and its potential to synergize with anti-cancer drugs

Abstract

Safingol is a sphingolipid with promising anti-cancer potential which is currently in Phase I clinical trial. Yet, the underlying mechanisms of its action remain largely unknown. The research presented in this thesis focused on elucidating the mechanism of safingol and its potential to synergize with conventional anti-cancer drugs. It is demonstrated that safingol/irinotecan combination was synergistic in colon cancer cells, and modulation of protein kinase C pathway could be a possible molecular basis for the observed synergism. As a single agent, safingol treatment triggered the generation of reactive oxygen species which appeared to be a critical mediator of safingol-induced autophagy and necrotic cell death. By understanding its molecular effects, safingol-based, anti-cancer drug combinations could be appropriately identified for effective treatment. In summary, this research provides new insights into the molecular mechanism of safingol, and supports its therapeutic use to synergize with other anti-cancer drugs.