Antiproliferative effects of the natural oxadiazine nocuolin A are associated with impairment of mitochondrial oxidative phosphorylation

Natural products are interesting sources for drug discovery. The natural product oxadiazine Nocuolin A (NocA) was previously isolated from the cyanobacterial strain Nodularia sp. LEGE 06071 and here we examined its cytotoxic effects against different strains of the colon cancer cell line HCT116 and the immortalized epithelial cell line hTERT RPE-1. NocA was cytotoxic against colon cancer cells and immortalized cells under conditions of exponential growth but was only weakly active against non-proliferating immortalized cells. NocA induced apoptosis by mechanism(s) resistant to overexpression of BCL family members. Interestingly, NocA affected viability and induced apoptosis of HCT116 cells grown as multicellular spheroids. Analysis of transcriptome profiles did not match signatures to any known compounds in CMap but indicated stress responses and induction of cell starvation. Evidence for autophagy was observed, and a decrease in various mitochondrial respiration parameter within 1h of treatment. These results are consistent with previous findings showing that nutritionally compromised cells in spheroids are sensitive to impairment of mitochondrial energy production due to limited metabolic plasticity. We conclude that the antiproliferative effects of NocA are associated with effects on mitochondrial oxidative phosphorylation.

This research was supported by the Structured Program of R&D&I INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR), funded by the Northern Regional Operational Program (NORTE2020) through the European Regional Development Fund (ERDF). The project was additionally supported the project CYANCAN - Uncovering the cyanobacterial chemical diversity: the search for novel anticancer compounds (reference PTDC/MEDQUI/30944/2017) co-financed by NORTE 2020, Portugal 2020, and the European Union through the ERDF, and by Foundation for Science and Technology through national funds. RU was supported by the FCT postdoc grant SFRH/BPD/112287/2015 and MS by the FCT PhD grant SFRH/BD/108314/2015.