Endocrine/Head and Neck
Kristen E. Limbach, MD
Fellow Physician
City of Hope National Medical Center - Duarte, CA
Duarte, California, United States
Disclosure: Disclosure information not submitted.
Limited systemic therapy options exist for advanced pancreatic neuroendocrine tumors (PNETs), but mTOR inhibition has been shown to prolong progression free survival. The natural compound baicalein inhibits mTOR and may have antiproliferative effects in PNETs at high concentrations. However, it is unknown if baicalein exhibits such effects at physiologically achievable concentrations and whether it exhibits synergy with other agents.
Methods: PNET cell lines BON-1 and QGP-1 were cultured with 4-40 µM baicalein, 0.4-2.0 µM everolimus, and 1-4 µM of a synthetic AMPK activating agent, COH-SR4, alone and in combination. Cell viability assays and immunoblotting were performed. Female SCID-beige mice were injected with BON-1 cells and treated with baicalein and COH-SR4 solutions via oral gavage. Tumor volumes were measured at 30 days and compared using t-test. Synergy was calculated using the Chou-Talalay method.
Results: Immunoblotting revealed that treatment of baicalein induced AMPK activation and subsequent mTOR inhibition at 24 hours in a dose dependent fashion in both BON-1 and QGP-1 cell lines. Treatment of these lines with baicalein alone led to a significant decrease in the ratio of viable cells compared with controls at 72 hours at concentrations ≥5 µM (p=0.021). Combination of baicalein with a synthetic AMPK activating agent, COH-SR4, led to significantly greater effect on cell viability in both cell lines than with baicalein alone (p< 0.001, p< 0.001) or with COH-SR4 alone (p=0.004, p=0.015), and synergy was observed. Combination of baicalein at concentrations of 20-40 µM with everolimus resulted in significantly lower cell viability in BON-1 cells than with everolimus alone (p=0.005, p< 0.001). Tumor volume in vivo was significantly decreased with the combination of baicalein and COH-SR4 compared with controls (p=0.003).
Conclusions: Baicalein exhibits antiproliferative effects against PNET cell lines at doses as low as 5 µM, which are likely physiologically achievable, and demonstrates synergy with other AMPK activating agents, making it a promising agent for further study.