Scytophycins, including tolytoxin, represent a class of actin disrupting macrolides with strong antiproliferative effects on human cells. Despite intense research, little attention has been paid to scytophycin-induced cell death or the structural features affecting its potency. We show that tolytoxin and its natural analogue, 7-O-methylscytophycin B, lacking the hydroxyl substitution in its macrolactone ring, differ substantially in their cytotoxic effect. Both compounds increase the level of caspases 3/7, which are the main executioner proteases during apoptosis, in HeLa wild-type (WT) cells. However, no caspase activity was detected in HeLa cells lacking Bax/Bak proteins crucial for caspase activation via the mitochondrial pathway. Obtained data strongly suggests that scytophycins are capable of inducing mitochondria-dependent apoptosis. These findings encourage further research in structure-activity relationships in scytophycins and highlight the potential of these compounds in targeted drug delivery.

CZ OPENSCREEN National Infrastructure for Chemical Biology Institute of Molecular Genetics of the ASCR v v i 142 20 Prague 4 Czech Republic

Faculty of Science University of South Bohemia in České Budějovice Branišovská 1760 37005 České Budějovice Czech Republic

Institute of Biophysics Biological Research Center 6726 Temesvári krt 62 Szeged Hungary

Institute of Microbiology of the Czech Academy of Sciences Center Algatech Novohradska 237 37981 Trebon Czech Republic

Laboratory of Molecular Structure Characterization Institute of Microbiology Academy of Sciences of the Czech Republic Videnska 1083 142 20 Prague Czech Republic

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