Abstract 611: Actinobacteria from macroalgae as a source of new anti-lymphoma compounds

Abstract Background: Actinomycetota of the genus Streptomyces are well known to produce a wide range of secondary metabolites, many of which have already been developed into antibiotics, antifungals, anti-inflammatory compounds, and anticancer agents. They can be found in the marine environment, including the deep sea, and are frequently associated with marine organisms, such as macroalgae. We studied the anti-lymphoma activity of extracts from Actinomycetota isolated from several deep-sea samples and macroalgae species abundant along the Portuguese coast. Methods: Organic extracts were made from 7-day cultures using a 1:1 (v/v) methanol:acetone mix. An LC-MS/MS-based dereplication was applied to the extracts presenting the most relevant properties, using GNPS to identify the ones putatively containing novel molecules. Cancer cell lines were treated with each extract for 72h followed by MTT. Results: Actinomycetota strains were isolated from the tissues of 3 macroalgae species collected on the northern Portuguese coast (Laminaria ochroleuca, Chondrus crispus, Codium tomentosum) and from sediments, corals, and sponges from deep-sea regions. 147 extracts were tested (1 and 10 μg/ml) in marginal zone lymphoma (MZL) cell lines with acquired resistance to PI3K (n.=2), BTK (n.=1), and PI3K/BCL2 (n.=1) inhibitors and their parental counterparts (n.=2). 18 extracts gave broad-activity in at least 4/6 cell lines tested. Among those, we identified molecules present in more than 1 fraction, such as Apoptolidin A, known to have a cytotoxic effect in cancer cells. All extracts were MS tested to know the compositions of known molecules or analogs. Among the active extracts, we have identified some containing known molecules with unknown functions or unknown molecular entities with a broad anti-cancer effect. Twenty-three extracts showed different activity in parental and resistant cell lines. Thirty extracts with broad anti-cancer activity or different activity between parental and resistant were further validated in a larger dose-response curve. Seven were confirmed to have a higher activity in resistant than parental cells or broad antitumoral activity. Three extracts from seaweeds, M15 and M16 (from Streptomyces) and M28 (Verrucosispora sp) were selected for up-scaling culture and further fractionation in 13, 12, and 11 fractions, respectively. Activity was confirmed in some fractions at 10 μg/ml and for some M28-derived fractions at 1 μg/ml. M28 (containing no known compounds) and M15 showed a higher activity in resistant than parental models. Conclusions: We identified Actinobacteria extracts with broad anti-lymphoma activity or showing increased activity in MZL cells with acquired resistance to FDA-approved compounds compared to parental cells. Some fractions were composed of new molecular entities, representing potential sources of novel therapeutic compounds. Citation Format: Filippo Spriano, Alberto J. Arribas, Nikolai Bendik, Mariana Girão, Inês Ribeiro, Maria de Fátima Carvalho, Francesco Bertoni, Pedro Leão. Actinobacteria from macroalgae as a source of new anti-lymphoma compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 611.