Preclinical data supporting the flavone baicalein as a novel mTOR inhibitor with potent activity against endometrial cancer cells

Abstract

Objectives: The mTOR pathway is a promising target for endometrial cancer therapy commonly because of the loss of PTEN expression. Metformin has been shown to inhibit endometrial cancer cell proliferation and is currently in phase II/III clinical trial testing. We have identified a natural flavone, baicalein, which markedly upregulates DNA Damage Induced Transcript 4 (DDIT4), suppresses breast and ovarian cancer cell growth, and alters mTOR pathway. We examined the activity of baicalein in endometrial cancer cells. Methods: The endometrial cancer cell line HEC1a was treated with baicalein (5–80 μM) or metformin (5–10,000 μM) and growth was assessed at 24 to 72 hours with the MTT assay. Total protein lysates were obtained for Western blot analysis to evaluate mTOR pathway mediators and DDIT4 levels. In vivo studies were performed with an HEC1a mouse model. Mice received either control or baicalein (80 mg/kg) treatment by oral gavage daily. Tumor volumes were measured over time. Results: Baicalein inhibited growth of HEC1a cell line in a dose-dependent fashion (IC50 ~10 μM). In contrast, higher millimolar concentrations (>1,000-fold) were required to inhibit growth with metformin. The observed growth inhibition with baicalein was associated with decreased PS6K1 and PS6 levels and increased DDIT4 levels. We tested baicalein (80 mg/kg) in an endometrial cancer cell mouse model. We observed significant tumor growth inhibition in the HEC1A mouse model compared with control mice. (See Fig. 1.) Conclusions: Both in vitro and in vivo studies support baicalein as a potent inhibitor of endometrial cancer cell proliferation. The inhibitory effect correlates with mTOR pathway inhibition and increase in DDIT4 expression. This preclinical study supports the use of baicalein as a novel treatment for endometrial cancer.