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Organic cation transporter (OCT) function is critical for cellular homeostasis.  C. elegans  lacking OCT-1 displays a shortened lifespan and increased susceptibility to oxidative stress. We show that these phenotypes can be rescued by downregulating the OCT-1 paralogue, OCT-2. Herein, we delineate a biochemical pathway in  C. elegans  where uptake of genotoxic chemotherapeutics such as doxorubicin and cisplatin, and subsequent DNA damage-induced apoptosis of germ cells, are dependent exclusively upon OCT-2. We characterized OCT-2 as the main uptake transporter for doxorubicin, as well as a number of other therapeutic agents and chemical compounds, some identified through ligand-protein docking analyses. We provide insights into the conserved features of the structure and function and gene regulation of  oct-1  and  oct-2  in distinct tissues of  C. elegans . Importantly, our innovative approach of exploiting  C. elegans  uptake transporters in combination with defective DNA repair pathways will have broad applications in medicinal chemistry.

A novel approach using C. elegans DNA damage-induced apoptosis to characterize the dynamics of uptake transporters for therapeutic drug discoveries