Fig. 5

The summary of chemo-radio effect of metformin. After administration, the hypoglycemic effect of metformin decreases insulin level and inhibits insulin-like growth factor (IGF) signaling pathway as the indirect anticancer effect. In the direct anticancer pathways, metformin is transported by OCT-1 and OCT-3 to mitochondria, inhibits the ETC to generate ATP, and preserves oxygen. The ATM, LKB1, and AMPK pathway illustrate the anticancer effects on p53 and mTOR. The inhibition on mTOR to HIF-1α, free radicals generation, and ROS illustrate the regulatory effects of metformin on radio-refractory cancer cells. The green arrow means enhance or upregulate; the red arrow means inhibit or downregulate