Beta-sitosterol-baicalein-guanosine synergistically alleviates Warburg effect in colorectal cancer via EGFR/ERK pathway.

[OBJECTIVES] This study investigated whether the active ingredients of Pinellia pedatisecta Schott extract (PE) inhibit colorectal cancer (CRC) by targeting the Warburg effect, a common cancer hallmark, and to elucidate the involved mechanism.

[METHODS] The active ingredients of PE were identified by high performance liquid chromatography (HPLC). The efficacy of the beta-sitosterol (BS), baicalein, and guanosine (Guo) combination was then evaluated in vivo. In vitro, cell viability, migration, and invasion capabilities were investigated by CCK-8, scratch assay, and Transwell assays, respectively. Network pharmacology was employed to identify potential targets related to the Warburg effect, which were subsequently validated in vitro.

[KEY FINDINGS] HPLC identified three active ingredients in PE: BS, baicalein, and Guo. The mice exhibited tumor weight loss and volume reduction after BS-baicalein-Guo treatment. In addition, BS-baicalein-Guo elevated apoptosis of HCT-116 cells, while significantly reducing their proliferation in vivo. Besides, BS-baicalein-Guo diminished glucose uptake, lactate and ATP, as well as the expression of glycolysis-related proteins (HK2 and PKM2) and extracellular signal-regulated kinase (ERK) and epidermal growth factor receptor (EGFR) phosphorylation in HCT-116 cells, while NSC228155 (EGFR activator) ameliorated these phenomena.

[CONCLUSIONS] The BS-baicalein-Guo combination synergistically alleviates the Warburg effect in CRC by suppressing the EGFR/ERK pathway, highlighting its potential as a therapeutic target.