Microcystins as novel leads against OATP1B3-expressing tumors

Microcystins are cyclic heptapeptides produced by cyanobacteria. They potently inhibit the eukaryotic protein phosphatase families PP1 and PP2A. They are able to display toxicity only after transporter-mediated uptake by the cell. This uptake is mediated by the organic anion transporting polypeptides OATP1B1, OATP1B3, and OATP1A2. Liver cells express OATP1B1 and OATP1B3 transporters, which results in a pronounced liver toxicity of microcystins. However, OATP1B3 is also expressed in a significant percentage of hepatocellular carcinoma cells as well as gastrointestinal, lung, breast and colon tumors. Interestingly, compared to OATP1B1, OATP1B3 is found only in low abundance in liver cells. Thus selectivity that favors OATP1B3 over OATP1B1 should lead to a decreased hepatic clearance and toxicity, and an increased uptake in OATP1B3-expressing tumors, thus creating a therapeutic window for the respective compound.

Since many naturally occurring microcystin variants are known and many more have not been described yet, there is high potential for isolating variants with unique properties. In fact, in our initial screening of 20 microcystins, we have found four microcystin structural variants with an IC₅₀ in the low nanomolecular range and with transporter selectivity that favors OATP1B3 over OATP1B1 by a factor of more than ten. Some of these microcystin variants have not yet been described in the literature.