Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside?

Abstract

Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This action is most often attributed to a well-documented blockage of oxidative phosphorylation (OXPHOS) caused by a direct interference of metformin on Complex I function. Nevertheless, several other pleiotropic actions seem to contribute to the anticancer potential of this biguanide. In particular, in vitro and in vivo experimental studies recently documented that metformin selectively inhibits the uptake of 2-[18F]-Fluoro-2-Deoxy-D-Glucose (FDG), via an impaired catalytic function of the enzyme hexose-6P-dehydrogenase (H6PD). H6PD triggers a still largely uncharacterized pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER) that has been found to play a pivotal role in feeding the NADPH reductive power for both cellular proliferation and antioxidant responses. Regardless of its exploitability in the clinical setting, this metformin action might configure the ER metabolism as a potential target for innovative therapeutic strategies in patients with solid cancers and potentially modifies the current interpretative model of FDG uptake, attributing PET/CT capability to predict cancer aggressiveness to the activation of H6PD catalytic function.

6-Shogaol Antagonizes the Adipocyte-Conditioned Medium-Initiated 5-Fluorouracil Resistance in Human Colorectal Cancer Cells through Controlling the SREBP-1 Level

“…AMPK, an intracellular energy sensor and controller, has been originally served as a therapeutic target for the treatment of diabetes [ 30 ]. However, the regulation of AMPK signaling has also been further reported to potentiate the cytotoxicity and efficacy of anticancer drugs in treating patients with different types of cancers [ 31 , 32 ].…”

“…However, the regulation of AMPK signaling has also been further reported to potentiate the cytotoxicity and efficacy of anticancer drugs in treating patients with different types of cancers [ 31 , 32 ]. Moreover, this is also because of its energy homeostasis regulatory mechanism [ 30 ]. It has been shown that (i) AMPK activation by adding the AICAR, an agonist, significantly increasing the efficacious treatment for lethal breast cancer [ 31 , 32 ]; (ii) AMPK activation could promote the mitochondrial activity to increase the treating sensitivity in patients with myeloid leukemia [ 33 ]; (iii) AICAR activates the AMPK signaling to enhance the anticancer effect of chemotherapeutic agents in prostate cancer cells [ 34 ].…”

Metformin Intervention—A Panacea for Cancer Treatment?

“…Metformin is able to directly and indirectly interact with many enzymes, such as mitochondrial electron transport chain (ETC) complex I, adenosine 5′-monophosphate-activated protein kinase (AMPK), glycerol 3-phosphate dehydrogenase, fructose 1-6-bisphosphatase, and glucose 6P-phosphatase, which highlights the metabolic properties of metformin [ 15 , 35 , 36 , 37 , 38 , 39 , 40 ]. Metformin’s influence on multiple metabolic pathways is produced by targeting ETC complex I, the inhibition of which leads to subsequent AMPK activation [ 41 , 42 , 43 ].…”

Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review)

“…PPP may be a critical pathway in lipogenesis. In a recent study on cancer cells, metformin was reported to interfere with several enzymes related to PPP and decreased the effect of PPP via modulation of mTORC (74). However, the information about the association between metformin and 6PGD remains unclear (74).…”

“…In a recent study on cancer cells, metformin was reported to interfere with several enzymes related to PPP and decreased the effect of PPP via modulation of mTORC (74). However, the information about the association between metformin and 6PGD remains unclear (74). Briefly, in vitro, in vivo, or clinical trials have provided evidence that AMPK activation may be a critical step in improving lipid metabolism.…”