Abstract
Marine holobionts are an important source of bioactive natural products. Building on our previous studies of cytotoxic compounds from zoantharians of the genus Palythoa, we investigated the anticancer potential of bacteria associated with Palythoa variabilis. Ten culturable bacterial strains were isolated and screened for cytotoxic activity against metastatic prostate cancer cells (PC-3/M) using the MTT assay. Among them, the crude extract of strain BRA-035, identified as Streptomyces sp., showed the most promising bioactivity profile and was selected for cytotoxicity-guided fractionation. This approach enabled the isolation of piericidin A1 (1) and the identification of two additional piericidin derivatives (2 and 3). piericidin A1 exhibited strong and selective cytotoxicity, with IC(50) values ranging from picomolar to low nanomolar concentrations against ovarian (OVCAR), prostate (PC-3 and PC-3/M), and colorectal (HCT-116) tumor cell lines, while remaining inactive (IC(50) > 12 µM) against HL-60 leukemia and B16-F10 murine melanoma cells. Additional assays assessing cell proliferation and membrane integrity provided further insight into differential cellular sensitivity. Overall, these results demonstrate that P. variabilis-associated bacteria are a valuable source of bioactive metabolites and reinforce the translational potential of piericidin A1 as a promising anticancer drug candidate.