Serendipitous Discovery of Leucine and Methionine Depletion Agents during the Search for Polyamine Transport Inhibitors

Targeting
polyamine metabolism is a proven anticancer strategy.
Cancers often escape the polyamine biosynthesis inhibitors by increased
polyamine import. Therefore, there is much interest in identifying
polyamine transport inhibitors (PTIs) to be used in combination therapies.
In a search for new PTIs, we serendipitously discovered a LAT-1 efflux
agonist, which induces intracellular depletion of methionine, leucine,
spermidine, and spermine, but not putrescine. Because S-adenosylmethioninamine is made from methionine, a loss of intracellular
methionine leads to an inability to biosynthesize spermidine, and
spermine. Importantly, we found that this methionine-depletion approach
to polyamine depletion could not be rescued by exogenous polyamines,
thereby obviating the need for a PTI. Using 3H-leucine
(the gold standard for LAT-1 transport studies) and JPH-203 (a specific
LAT-1 inhibitor), we showed that the efflux agonist did not inhibit
the uptake of extracellular leucine but instead facilitated the efflux
of intracellular leucine pools.