Metformin as an Alternative Radiosensitizing Agent to 5FU During Neoadjuvant Treatment for Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiation for locally advanced rectal cancer combining 5FU to radiation increases tumor regression compared to radiation alone. However, it occurs at the cost of significant treatment-related toxicity. Patients with rectal cancer using metformin have been associated with improved response to radiotherapy. OBJECTIVE: To evaluate the radiosensitizing effects of metformin in vitro and in vivo and compare it to standard combination of radiation/5FU. DESIGN: Colorectal cancer cell lines SW480, HT29, and HCT116 were used as models. Cell viability was compared under treatments with radiation, radiation/5FU, metformin, radiation/metformin, and radiation/5FU/metformin. Nude mice were injected subcutaneously with SW480 cells and treated for one week with radiation/5FU, metformin, radiation/metformin or radiation/5FU/metformin. Tumor volume was evaluated for 4 weeks after treatment completion. The phosphorylation status of key proteins of the PI3K/Akt/mTOR pathway was determined by immunoblots. SETTINGS: Experimental study in vitro and in vivo. PATIENTS: Animal model/cell lines. MAIN OUTCOME MEASURES: The end point was to investigate how metformin compares to 5FU as a radiosensitizer. RESULTS: All cell lines significantly decreased cell viability after treatment with radiation/metformin when compared to radiation alone. Radiation/metformin was superior to radiation/5FU in SW480 (37% vs 74%; p 0.05), and that the addition of metformin to the standard radiation/5FU did not improve tumor response (349mm, p>0.05). Metformin exerted strong PI3K/Akt/mTOR pathway inactivation effects after 24-hour exposure (increasing pAMPK p<0.01, decreasing pAkt, p<0.01; and pS6, p<0.05). LIMITATIONS: In vitro and in vivo CRT regimens cannot be directly translated to human delivery methods. CONCLUSIONS: Metformin enhances tumor response to radiation in vitro and in vivo. Metformin is an attractive alternative radiosensitizing agent to be considered in future studies/trials. See Video Abstract at http://links.lww.com/DCR/B219.