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

Sci Rep. 2016 Oct 27;6:36026. doi: 10.1038/srep36026.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans Proteins
  • DNA Damage*
  • Drug Discovery / methods*
  • Membrane Transport Proteins / deficiency*
  • Mutagens / metabolism*
  • Organic Cation Transporter 2 / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Membrane Transport Proteins
  • Mutagens
  • OCT-1 protein, C elegans
  • Organic Cation Transporter 2