Bromoditerpenes from the red seaweed Sphaerococcus coronopifolius as potential cytotoxic agents and proteasome inhibitors and related mechanisms of action

Seaweeds are a great source of compounds with cytotoxic properties with the potential to be used as anticancer agents. This study evaluated the cytotoxic and proteasome inhibitory activities of 12R-hydroxy-bromosphaerol, 12S-hydroxy-bromosphaerol, and bromosphaerol isolated from Sphaerococcus coronopifolius. The cytotoxicity was evaluated on malignant cell lines (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, and SK-MEL-28) using the MTT and LDH assays. The ability of compounds to stimulate the production of hydrogen peroxide (H2O2) and to induce mitochondrial dysfunction, the externalization of phosphatidylserine, Caspase-9 activity, and changes in nuclear morphology was also studied on MCF-7 cells. The ability to induce DNA damage was also studied on L929 fibroblasts. The proteasome inhibitory activity was estimated through molecular docking studies. The compounds exhibited IC50 values between 15.35 and 53.34 μM. 12Rhydroxy-bromosphaerol and 12S-hydroxy-bromosphaerol increased the H2O2 levels on MCF-7 cells, and bromosphaerol induced DNA damage on fibroblasts. All compounds promoted a depolarization of mitochondrial membrane potential, Caspase-9 activity, and nuclear condensation and fragmentation. The compounds have been shown to interact with the chymotrypsin-like catalytic site through molecular docking studies; however, only 12S-hydroxy-bromosphaerol evidenced interaction with ALA20 and SER169, key residues of the proteasome catalytic mechanism. Further studies should be outlined to deeply characterize and understand the potential of those bromoditerpenes for anticancer therapeutics.

Description

This work was funded by the Portuguese Foundation for Science and Technology (FCT) through the strategic projects granted to the MARE—Marine and Environmental Sciences Center (UIDP/04292/2020; UIDB/04292/2020), the BioISI—BioSystems and Integrative Sciences Institute (UIDP/Multi/04046/2020; UIDB/04046/2020), iMed. ULisboa (UIDB/04138/2020; UIDP/04138/2020), and the Associate Laboratory ARNET (LA/P/0069/2020). FCT also support this study through the POINT4PAC project (SAICTPAC/0019/2015-LISBOA- 01-0145-FEDER-016405) and through the PDTC/QEQ-MED/7042/2014 and CROSS-ATLANTIC project (PTDC/BIA-OUT/29250/2017), co-financed by COMPETE (PO-CI-01-0145-FEDER-029250). The Spanish part was funded by Conselleria de Cultura, Educacion e Ordenación Universitaria, Xunta de Galicia, GRC (ED431C 2021/01). This work was also supported by the FCT and CAPES cooperation agreement through the project MAr-Tics (FCT/DRI/CAPES 2019.00277.CBM). Rebeca Alvariño is supported by a fellowship from Xunta de Galicia (ED481B-2021-038), Spain.

Keywords

Terpenes Algae Marine natural products Apoptosis Mitochondrial dysfunction Oxidative stress Anticancer Sphaerococcus coronopifolius

URI

http://hdl.handle.net/10400.8/8694

Citation

Alves, C.; Silva, J.; Pintéus, S.; Guedes, R.A.; Guedes, R.C.; Alvariño, R.; Freitas, R.; Goettert, M.I.; Gaspar, H.; Alfonso, A.; et al. Bromoditerpenes from the Red Seaweed Sphaerococcus coronopifolius as Potential Cytotoxic Agents and Proteasome Inhibitors and Related Mechanisms of Action. Mar. Drugs 2022, 20, 652. https://doi.org/10.3390/md20100652