Herniarin, a Natural Coumarin, Inhibits Mammary Carcinogenesis by Modulating Liver X Receptor-α/β-PI3K-Akt-Maf1 Pathway in Sprague-Dawley Rats

Background: The massive tumor burden following breast cancer initiation requires a constant supply of energy achieved by modification of different metabolic pathways. Enhanced lipid synthesis associated with glucose metabolism modification triggered by a battery of signaling events promotes unregulated cell division and growth. Coumarins with their diversified bioactivity are also recognized for their therapeutic efficacy in breast cancer. Objectives: Thus, this study was performed to assess the chemotherapeutic potential of herniarin (HER), a 7-methoxycoumarin derivative against polycyclic aromatic hydrocarbon-induced mammary cancer. Materials and Methods: In silico molecular docking was carried out to identify the interactions of HER with LXR alpha and beta, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR), PI3K, and Akt followed by in vitro evaluation of HMGCoAR inhibitory potential of HER. Detailed in vivo studies was then performed in 7,12-dimethylbenz(a) anthracene-induced breast cancer model in Sprague-Dawley (SD) rats using HER at doses 20 mg/kg, b. w. and 40 mg/kg, b. w. along with molecular-level analysis (messenger RNA and proteins) by real-time quantitative polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Results: The docking studies revealed a significant binding affinity of HER to the aforesaid receptors and its HMGCoAR inhibitory potential (IC50 = 103.1 nM) validated the docking studies. HER successfully re-established the lipid and lipoprotein levels along with the activities of lipid-metabolizing enzymes and glycolytic enzymes that were altered following cancer induction. The molecular biology evaluations reflected the efficiency of HER as it evidently alleviated the overexpression of HMGCOAR, PI3K, and Akt along with the lipogenic genes fatty acid synthase and acetyl-CoA carboxylase 1 in the carcinoma-developed animals by upregulating LXR (alpha and beta) and Maf1. Conclusion: The bioactive moiety HER efficiently controlled alterations in metabolic pathways, thus balancing energy consumption, attenuating tumor progression through LXR/PI3K/Akt/Maf1 axis in breast cancer in SD rats.