Synergistic Anticancer Effect of Luteolin and Etoposide via the PI3K/AKT Signaling Pathway

Etoposide (VP-16) is a widely used chemotherapeutic agent, but its efficacy is limited by toxicity and resistance. Luteolin (LUT), a natural flavonoid, exhibits antitumor activity and may enhance chemotherapy through signaling modulation. This study explores the synergistic effects of LUT and VP-16 and the underlying mechanism.

The H22 and 4T1 mouse tumor cells, as well as the human hepatocellular carcinoma cell line Huh7, were treated with LUT, VP-16, or their combination. The cell viability, colony formation, and apoptosis were evaluated by CCK-8 assay, crystal violet staining, and TUNEL assay, and the synergistic effect was analyzed using the combination index. The involvement of the PI3K/AKT signaling pathway was detected by Western blotting, and the agonist rescue experiment was conducted for verification. Antitumor efficacy and systemic toxicity were further evaluated in a subcutaneous xenograft mouse model.

LUT and VP-16 combination significantly inhibited proliferation and clonogenic potential while promoting apoptosis in all tested cell lines (P < 0.01). Western blotting showed suppression of PI3K and AKT phosphorylation, effects reversed by 740 Y-P. In vivo, the combination produced the strongest tumor reduction with enhanced apoptosis and reduced PI3K/AKT activation.

The synergistic effect of LUT and VP-16 is largely mediated by PI3K/AKT pathway inhibition, providing mechanistic insight into their combined antitumor action and suggesting a strategy to enhance chemotherapy efficacy.

LUT enhances the antitumor efficacy of VP-16 by synergistically inhibiting the PI3K/AKT signaling pathway. This combination presents a promising therapeutic strategy for improving chemotherapy outcomes in solid tumors.