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Abstract
Introduction Loss of PTEN expression is common in endometrial cancer. The PI3K/mTOR pathway has been a target, but counter-regulatory pathways via Akt and ERK may hinder efficacy. We previously showed that the natural flavonoid baicalein inhibits cell growth via mTOR pathway. We investigated the effects of a novel AMPK activator SR04 in combination with baicalein in endometrial cancer.
Methods Endometrial cancer cell lines, RL95–2 and KLE were treated with varying concentrations of baicalein and SR04. Cell viability assessment at 72 hours was determined by MTT assay. Drug combination studies and synergy quantification was performed using Chou-Talalay method. Western blot analysis was utilized to evaluate PI3K/mTOR end targets.
Results Baicalein or SR04 alone inhibited proliferation of endometrial cancer cell lines in a dose dependent manner. In combination, baicalein and SR04 acted synergistically to inhibit cell proliferation, especially at low concentrations (figure 1). The synergistic effect was mediated by inhibition of STAT3 and PS6 as demonstrated on Western blot (figure 2). Interestingly compensatory activation of AKT and MAPK pathways, which can oppose the anti-proliferative effects of PI3K/mTOR inhibition, was not observed with the combination of baicalein and SR04 on Western blots.
Conclusion/Implications The combination of baicalein and AMPK activator SR04 inhibits endometrial cancer cell proliferation in a synergistic manner. The combination does not appear to activate AKT and MAPK pathways which can hinder efficacy. The combination of baicalein and SR04 may offer a novel treatment paradigm for endometrial cancer.
