title: A novel approach using C. elegans DNA damage-induced apoptosis to characterize the dynamics of uptake transporters for therapeutic drug discoveries.
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.
authors: Maisonneuve-Rosemont Hospital, Research Center, Université de Montréal, Department of Medicine, 5415 Boul. de l' Assomption, Montréal, Québec H1T 2M4, Canada.
authors: Arturo
authors: A
authors: Papaluca
authors: Maisonneuve-Rosemont Hospital, Research Center, Université de Montréal, Department of Medicine, 5415 Boul. de l' Assomption, Montréal, Québec H1T 2M4, Canada.
authors: Dindial
authors: D
authors: Ramotar
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000187:drug effects*; D029742:Caenorhabditis elegans Proteins; D004249:DNA Damage; D055808:Drug Discovery / Q000379:methods*; D026901:Membrane Transport Proteins / Q000172:deficiency*; D009153:Mutagens / Q000378:metabolism*; D000075102:Organic Cation Transporter 2 / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D026901:Membrane Transport Proteins; D009153:Mutagens; C000607157:OCT-1 protein, C elegans; D000075102:Organic Cation Transporter 2