Potential applications for biguanides in oncology

Abstract

Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.

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Figure 1. Systemic effects of biguanides.

Following oral administration, biguanides have local effects on the GI tract, including the colon, as the luminal concentration can exceed the serum concentration. This elevated concentration may explain observed antiproliferative effects of metformin on colon epithelial cells (92, 93). Absorbed drugs are initially routed to the liver via the portal circulation, and this organ is exposed to high concentrations relative to others, not only because it receives portal circulation, but also because hepatocytes express high levels of cell surface transport molecules such as OCT1 required for the import of biguanides such as metformin. In liver, gluconeogenesis is inhibited, leading to declines in circulating glucose and insulin, particularly in the setting of elevated baseline levels. A variety of actions may also occur in other organs, including potentially antiinflammatory actions (40), antiproliferative actions (21), prosurvival actions (83), and antiaging actions (22). However, these effects are dependent on adequate drug levels, and knowledge concerning organ-specific pharmacokinetics of metformin is incomplete.

Figure 2. Cellular effects of biguanides.

(i) Uptake of some biguanides, such as metformin, is dependent on specific transport molecules such as OCT1; other biguanides, such as phenformin, are more lipophilic and less dependent on active transport. (ii) Biguanides can be actively excreted, for example by multidrug and toxin extrusion (MATE) proteins. (iii) Biguanides are not homogeneously distributed within the cell; the mitochondrial membrane potential promotes increased uptake of biguanides, and mitochondria have the highest concentration. This is important, as key targets such as respiratory complex I, are in the mitochondria. Mitochondrial actions of biguanides reduce oxidative phosphorylation, resulting in decreased cellular ATP (iv), decreased NAD+ (v), and other derangements in mitochondrial metabolism. The reduction in ATP generation from oxidative phosphorylation leads to a compensatory increase in glucose uptake (vi) and glycolysis, with increased lactate secretion (vii). However, especially if glucose concentrations are limiting, this compensation is not sufficient to restore ATP to baseline levels. (viii) Therefore, if AMPK and its effectors are functional, AMPK activation results in reductions in energy expenditure and anabolic processes, leading to an antiproliferative (but potentially prosurvival) effect. (ix) On the other hand, in cancers with loss of function of AMPK or its key effectors, energy expenditure is not reduced despite reduced energy supply, leading to an energetic crisis.