Abrogation of microcystin cytotoxicity by MAP kinase inhibitors and N-acetyl cysteine is confounded by OATPIB1 uptake activity inhibition.

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Daily A, Monks NR, Leggas M, Moscow JA

Abrogation of microcystin cytotoxicity by MAP kinase inhibitors and N-acetyl cysteine is confounded by OATPIB1 uptake activity inhibition.

Toxicon. 2010 Apr 1;55(4):827-37. doi: 10.1016/j.toxicon.2009.11.019. Epub 2009 Nov 24.

PubMed ID

19944114 [ View in PubMed

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Abstract

Solute transporters that are selectively expressed on tumor cell membranes could be targeted with small molecule toxins that are selective substrates for these transporters. HeLa cells transfected to express the solute transporter OATP1B1 are exquisitely sensitive in vitro to microcystin LR (MCLR) and its analogs, and undergo rapid morphologic changes after exposure to MCLR. Immunoblot analyses revealed HSP27 phosphorylation increased prior to the rapid MCLR-induced morphologic changes. However, transfection of OATP1B1-expressing cells with HSP27 dominant negative mutants did not reverse MCLR toxicity. Although the MAP kinase p38 inhibitor SB202190 partially reversed MCLR cytotoxicity, the control molecule, SB202474, had similar effects. Unexpectedly, both SB202190 and SB202474 inhibited OATP1B1 uptake activity, indicating an alternative explanation for cytotoxicity reversal that did not involve p38 MAP kinase. Similarly, although the potassium chloride co-transporter (KCC) inhibitor (dihydro-indenyl)oxyalkanoic acid (DIOA), and the anti-oxidant, N-acetyl cysteine (NAC) both reversed MCLR cytotoxicity, both were also found to be unexpected OATP1B1 transport inhibitors. Therefore, the mechanism of MCLR-induced cytotoxicity is obscured by the inhibition of OATP1B1 uptake activity by MAP kinase inhibitors, DIOA, and NAC. Finally, growth of OATP1B1-expressing HeLa xenografts was inhibited by MCLR, suggesting that MCLR structural analogs selected for a broader therapeutic index could target OATP-expressing tumors.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Acetylcysteine	Solute carrier organic anion transporter family member 1B1	Protein	Humans	Unknown	Inhibitor	Details