Alpha lipoic acid modulates metabolic reprogramming in breast cancer stem cells enriched 3D spheroids by targeting phosphoinositide 3-kinase: In silico and in vitro insights

Breast cancer stem cells (BCSCs) are a unique subpopulation of tumor cells driving tumor resistance, progression, metastasis, and recurrence. Reprogrammed cellular metabolism and key signaling pathways, including Wnt/β-catenin, TGF-β, STAT3, and PI3K/AKT/mTOR pathway play a vital role in maintaining BCSCs. Importantly, PI3K/Akt/mTOR pathway regulates metabolism, survival, growth, and invasion, with PIK3CA, encoding the PI3K catalytic subunit p110α, the most frequently mutated gene in breast cancer. This study investigates the effects of alpha-lipoic acid (LA) on the metabolic profile of BCSCs, focusing on its interaction with PI3K signaling. LA was found to bind PI3K, disrupting cancer-associated metabolic pathways and significantly inhibiting BCSC metabolism. Metabolomic analysis of MCF-7 and MDA-MB-231-derived breast cancer spheroids showed LA-induced metabolic shifts. In MCF-7 spheroids, LA induced upaccumulation of 15 metabolites and downaccumulation of 5, while in MDA-MB-231 spheroids, it induced upaccumulation of 3 and downaccumulation of 16. LA also enhanced the sensitivity of breast cancer spheroids to doxorubicin (Dox), demonstrating a synergistic effect. Mechanistically, LA modulates the PI3K/Akt/mTOR pathway, impairing cell survival and proliferation. These findings highlight the potential of LA as a therapeutic agent for reprogramming cancer metabolism and enhancing chemotherapy efficacy. These results provide a strong rationale for incorporating LA into combination therapy strategies for breast cancer treatment.