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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Trends Cancer. 2021 Apr 14;7(8):714–730. doi: 10.1016/j.trecan.2021.03.001

Figure 1. Molecular targets of biguanides that underlie their anti-tumor activities.

Figure 1.

Biguanides enter cells either directly (phenformin) or via organic cation transporters (OCTs) (metformin), and target mitochondrial complex I, AMPK, mTOR and/or mGPD. Inhibition of mitochondrial complex I by biguanides triggers an increase in the AMP/ADP:ATP ratio, leading to activation of AMPK and subsequent attenuation of mTOR signaling. Biguanides also inhibit mGPD, leading to perturbation of the G3P shuttle and the accumulation of NADH and G3P. Finally, biguanides may activate AMPK and inhibit mTOR independent of mitochondrial complex I status by inducing the formation of v-ATPase-Ragulator-AXIN/LKB1-AMPK complex on lysosomal membranes.