Rerouting Chlorambucil to Mitochondria Combats Drug Deactivation and Resistance in Cancer Cells

SummaryThe difficulty of accessing the mitochondrial matrix has limited the targeting of therapeutics to this organelle. Here, we report, to our knowledge, the first successful delivery of an active DNA alkylating agent—chlorambucil—to mitochondria, and describe unexpected features that result from rerouting this drug within the cell. Mitochondrial targeting of this agent dramatically potentiates its activity, and promotes apoptotic cell death in a variety of cancer cell lines and patient samples. This retention of activity is observed even in cells with resistance to chlorambucil or disabled apoptotic triggering.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (446 K)Download as PowerPoint slideHighlights► Chlorambucil, retargeted from the nucleus to the mitochondria, retains selective activity against cancer cells ► To our knowledge, this is the first report of delivery of an active DNA-alkylation agent specifically to mitochondria ► Organellar targeting increases potency 100-fold but therapeutic window maintained ► Mitochondrial sequestration allows for evasion of drug resistance