title: Selectivity and potency of microcystin congeners against OATP1B1 and OATP1B3 expressing cancer cells.
abstract: Microcystins are potent phosphatase inhibitors and cellular toxins. They require active transport by OATP1B1 and OATP1B3 transporters for uptake into human cells, and the high expression of these transporters in the liver accounts for their selective hepatic toxicity. Several human tumors have been shown to have high levels of expression of OATP1B3 but not OATP1B1, the main transporter in liver cells. We hypothesized that microcystin variants could be isolated that are transported preferentially by OATP1B3 relative to OATP1B1 to advance as anticancer agents with clinically tolerable hepatic toxicity. Microcystin variants have been isolated and tested for cytotoxicity in cancer cells stably transfected with OATP1B1 and OATP1B3 transporters. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. As microcystin structure has a significant impact on transporter selectivity, it is potentially possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs.
authors.affiliation: Cyano Biotech GmbH, Berlin, Germany; Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Timo H J
authors.initials: TH
authors.lastname: Niedermeyer
authors.affiliation: Department of Pediatrics, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Abigail
authors.initials: A
authors.lastname: Daily
authors.affiliation: Cyano Biotech GmbH, Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Swiatecka-Hagenbruch
authors.affiliation: Department of Pediatrics, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Moscow
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D027381:Liver-Specific Organic Anion Transporter 1; D052998:Microcystins / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D052998:Microcystins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010456:Peptides, Cyclic; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C063998:nodularin; C078588:microcystin