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The yeast plasma membrane protein Agp2 belongs to the family of amino acid transporters. It acts as a regulator that controls the expression of several uptake transporter genes such as  DUR3  and  SAM3  encoding two high-affinity polyamine permeases.  agp2Δ  mutants display extreme resistance to several cationic compounds including polyamines, the anticancer agent bleomycin, and cationic antifungal peptides. We propose that Agp2 might be involved in regulating the uptake of other cationic anticancer drugs. To date, an uptake transporter has not been reported for anthracyclines, a family of chemotherapeutic agents that are used for treating adult patients with acute myeloid leukemia. Herein, we develop assay conditions to monitor the uptake of the anthracycline doxorubicin into yeast cells and demonstrate for the first time that Agp2 is required for the drug uptake. Deletion of both the  DUR3  and  SAM3  genes reduced doxorubicin uptake, but not the deletion of either gene alone, while the  agp2Δ  mutant was severely compromised, suggesting that Agp2 controls the drug uptake  via  Dur3 and Sam3 and at least one additional transporter. Overexpression of DUR3 or SAM3 from the endogenous promoter rescued doxorubicin uptake into the  sam3Δdur3Δ  double mutant, consistent with a role for these transporters in the uptake of anthracyclines. We further show by cross-species complementation analysis that expression of the  Caenorhabditis elegans oct-1  gene encoding an organic cation transporter restored full doxorubicin uptake in the  agp2Δ  mutant. Four separate variants of CeOCT-1 derived by substituting the amino acid residues Gln15, Cys31, Gln109 and Lys300 with alanine were stably expressed, but did not mediate doxorubicin uptake into the  agp2Δ  mutant. Moreover, we show that overexpression of CeOCT-1 sensitized parent yeast cells to doxorubicin, suggesting that CeOCT-1 related members might be key transporters to facilitate entry of anthracyclines into human cells.

Complementation of the Yeast Model System Reveals that Caenorhabditis elegans OCT-1 Is a Functional Transporter of Anthracyclines