A Novel Mechanism of High Dose Radiation Sensitization by Metformin
Conclusion
Radiosensitization by metformin has been demonstrated previously and attributed to the PI3K/AKT/mTOR pathway. Others proposed that metformin improves radiosensitization through improved oxygenation (2). In the current study, results support a possible third mechanism of radiosensitization by metformin based on the microenvironment, particularly glucose concentration at the time of metformin administration. Single high-dose radiation exposure leads to a profound decrease in tumor perfusion that could adversely affect the microenvironment and potentiate metformin cytotoxicity. Our on-going in vivo xenograft study indeed shows a preferential killing of cancer cells under conditions consistent with low oxygen and low glucose following a single high-dose of radiation therapy and metformin. Future work includes exploring (1) the optimum timing under fractionated high-dose radiation therapy, and (2) alternative strategies to reduce glucose in the microenvironment prior to metformin administration. Finally, the results of the current study have help explain the response of high dose radiotherapy used clinically for cancers of the brain (SRS) and other sites (SBRT), when cancer patients also have diabetes and are taking metformin.
Author Contributions
JK conceived the presented idea. JK, SB, AK, DI, KA, KL, and KJ planned the studies. AK, SB, DI, KA, KL, and KJ carried out the studies. JK, SB, AK, DI, KA, KL, and KJ contributed to interpretation of the results. JK and SB...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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