Brown alga Costaria costata as a source of phlorethol that inhibits TPA-induced neoplastic cell transformation and progression of human breast cancer cells via AKT/GSK-3(3/CDKs pathway

Phlorotannins are polyphenolic compounds synthesized by brown algae that have recently attracted great interest due to their unique structure, vast range of bioactivities, and potential applications in human health and nutrition. In the present study, the chemical structure of phlorethol from the brown alga Costaria costata (CcPh) is elucidated. Its effect and molecular mechanisms of anticancer action are assessed using the models of 12-Otetradecanoylphorbol-13-acetate (TPA)-induced tumorigenic transformation of mouse epidermal JB6 Cl41-5a cells and human triple-negative breast cancer MDA-MB-231 cells. It has been found that CcPh having a degree of polymerization of 12-25 phloroglucinol units and a molecular weight of 2520 Da, belong to the phlorethol class. CcPh shows cytotoxic activity against non-induced and TPA-induced JB6 Cl41-5a cells with IC50 = 97.1 f 3.0 and 114.3 f 2.2 mu g/mL, respectively, or MDA-MB-231 cells with IC50 = 95 f 1.2 and 109 f 7.5 mu g/ mL, respectively. CcPh effectively inhibits TPA-induced neoplastic transformation of JB6 Cl41-5a cells, colony formation, and migration of MDA-MB-231 cells through the inhibition of AKT and GSK-3(3 kinase phosphorylation and the regulation of cell cycle protein (CDK4, Cyclin D1, and p21) expression. These properties of phlorotannins provide a wide range of opportunities for the development of new approaches to prevention and therapy of highly aggressive forms of breast cancer in the future.