Cytotoxic Activity of LCS-1 is not Only due to Inhibition of SOD1

Abstract

Background: The cytotoxic activity of the pyridazin-3-one derivative LCS-1 was previously suggested to be due to the inhibition of superoxide dismutase 1 (SOD1). However, no direct evidence was provided that LCS-1 inhibits SOD1 within cells.

Methods: In this study, we investigated the cytotoxic activity of LCS-1 against bloodstream forms of Trypanosoma brucei, a protozoan parasite that does not express copper/zinc-containing SOD1, but an iron-containing superoxide dismutase (FeSOD).

Results: At 250 µM, LCS-1 did not inhibit the activity of FeSOD in cell lysates of bloodstream forms of T. brucei, confirming that the compound is a specific inhibitor of SOD1. However, LCS-1 displayed substantial trypanocidal activity with a minimum inhibitory concentration of 10 µM and a half-maximal effective concentration of 1.36 µM, indicating that the cytotoxic action of the compound cannot solely be due to inhibition of SOD1.

Conclusion: The results of this study is an important finding as it shows that LCS-1 has more than one cytotoxic mode of action.