Targeting the phosphoinositide 3-kinase signaling pathway and epidermal growth factor receptor: The potential of dimethylcardamonin-derived amino acids in triple-negative breast cancer therapy.

Targeting the phosphoinositide 3-kinase (PI3K) signaling pathway, along with the epidermal growth factor receptor (EGFR), presents a promising strategy for breast cancer treatment. Here, dimethylcardamonin (DMC, 1), isolated from Syzygium nervosum seeds, was modified by attaching amino acids such as serine (2h), tryptophan (2i), and tyrosine (2j) to produce new compounds. Compounds 2h-2j demonstrated most excellent inhibitory effectiveness against breast cancer cells, with IC values of 4.59 ± 0.06, 5.33 ± 0.59, and 6.89 ± 0.85 μM, respectively, in MDA-MB-231 cells. These DMC derivatives not only induced DNA damage but also triggered morphological changes in breast cancer cells. Notably, compound 2j increased sub-G0/G1 cell cycle accumulation and through the G2/M phase arrest, significantly inducing both early and late apoptosis. It also effectively reduced mitochondrial membrane potential alterations at higher concentrations. Furthermore, the compound 2j upregulated the expression of genes like Bax, BRCA1, Caspase-3, CDKN1A, Mcl-1, and PIK3CA, potentially influencing apoptosis via the PI3K/AKT pathway. The compound 2j significantly inhibited the MDA-MB-231 cells proliferation by downregulation of EGFR, p-EGFR, and p-AKT protein expression levels. Molecular docking studies revealed that compound 2j had a strong binding affinity and interacted closely with key catalytic residues of EGFR, outperforming erlotinib, a known EGFR inhibitor, suggesting its potential as an anti-breast cancer drug candidate.