A novel guaiane sesquiterpene derivative, guai-2-en-10 alpha-ol, from Ulva fasciata Delile inhibits EGFR/PI3K/Akt signaling and induces cytotoxicity in triple-negative breast cancer cells

摘要

A novel guaiane sesquiterpene derivative, guai-2-en-10 alpha-ol, from Ulva fasciata Delile exhibits antimicrobial property. U. fasciata extract was reported to exhibit cytotoxicity against cancer. In the present study, we have studied the anticancer potential of the compound, guai-2-en-10 alpha-ol, from U. fasciata. The compound showed selective cytotoxicity toward triple-negative breast cancer (TNBC) cell line (MDA MB-231) in a dose-dependent manner. In treated cells, the apoptotic hallmarks such as formation of apoptotic bodies, cell shrinkage, and nuclear condensation were observed. Many small molecules affect the function of cellular signaling pathways. As EGFR/PI3K/Akt pathway proteins are frequently altered in TNBC, we have studied the gene expression of key proteins of this pathway. The semiquantitative PCR results demonstrated the down-regulated expression of PDPK1 (positive regulator) and Akt (key activator) as well as up-regulated expression of PTEN (negative regulator), which suggested the interaction of guai-2-en-10 alpha-ol with upstream protein. Further investigation showed the down-regulation of both PI3K and EGFR. As EGFR is the most upstream protein of the pathway, its protein level expression was investigated. Western blotting analysis confirmed the down-regulation of p-EGFR expression and activation of apoptosis upon compound treatment. Cell cycle analysis also evidenced the G1 phase arrest, which can be due to the inhibition of cell survival pathway. Computational studies showed the interaction of guai-2-en-10 alpha-ol with Asp855 residue of EGFR kinase domain in active conformation. All these results demonstrate the anticancer potential of guai-2-en-10 alpha-ol through EGFR/PI3K/Akt pathway.