Identification of an Unsaturated Hydroxy Fatty Acid Antitumor Oxylipin from Brown Alga Scytosiphon lomentaria: (E)-6-Hydroxyoctadec-4-enoic Acid (NP-011548)

Marine brown algae are an important source of bioactive metabolites with promising anticancer potential. Scytosiphon lomentaria has repeatedly shown selective antitumor activity, although the active metabolite associated with its lipophilic fractions had not previously been identified. Here, five solvent extracts were screened and a bioassay-guided primary and secondary fractionation approach, using the less-active related species Scytosiphon dotyi as a comparator, was combined with high-resolution mass spectrometry to identify the oxylipin (E)-6-hydroxyoctadec-4-enoic acid (NP-011548) as a metabolite endowed with significant antitumor activity. The pure compound selectively reduced the viability of human breast (MDA-MB-231) and ovarian (Kuramochi) cancer cells while exhibiting limited toxicity towards normal fibroblasts. Comparative testing with the structural analogs 6-hydroxystearic acid (6-HSA) and 6-oxostearic acid (6-OSA) further indicated that the C4 double bond and the C6 hydroxy group may contribute to the selective activity of NP-011548. NP-011548 induced delayed reactive oxygen species accumulation without activating caspase-3/7 and caused extensive mitochondrial degeneration, lysosomal accumulation, chromatin condensation and plasma membrane alterations, supporting the involvement of a caspase-independent cell death. These findings identify NP-011548 as a candidate metabolite underlying the antitumor activity of S. lomentaria, expanding the biological relevance of marine oxylipins and supporting their potential as a source of novel anticancer agents.