EFFECTS OF BIGUANIDES ON THE IMMUNE SYSTEM
I IMMUNOSTIMULATION
It was suggested that MET may present antagonistic actions according to the pathological state of the submitted organism. In individuals with cancer, it has been shown to activate both the innate and the adaptive immune system. Such immuno-stimulatory effects were able to inhibit the progression of the tumor or even to eradicate it, besides producing an anti-metastatic effect in several animal models [45]. This immuno-stimulatory action was demonstrated in a series of studies chosen for this review and a detailed description of its effects was schematized in Chart 2.
MET has received considerable attention in the field of oncology since 2005, after epidemiological publication highlighting the reduction in the risk of neoplasias. From this, several observational studies corroborate the antineoplastic effects in diabetics, including liver, colorectal, pancreas, and stomach and esophagus cancer [24]. Anisimov (2015), in his meta-analysis, stated that after a single dose of MET, its peak plasma concentration in patients with DMT2 ranged from 4-15µM, and that most in vitro studies used doses of MET between 0.5-50 mM to suppress tumor growth, apparently much more than in humans. However, in vivo studies in several types of rats demonstrated an antitumor effect for several cancers with doses lower than 500 mg/kg, a value that produces plasma concentration equivalent to that produced by the maximum dose in humans (2500 mg/kg), comparing the body surface and weight of mice with 20g and human with 60kg [68].
The mechanisms associated with the benefits of MET against cancer continue to be discussed [20]. The decrease in the production of ATP induced by the drug may be intolerable for cells sensitive to energy stress, and may lead to cell apoptosis [46, 47]. The consequent lower production of ROSs is one of the mechanisms that lead to a lower incidence of cancer, activating AMPK and its related pathways [49]. Pryor and Cabreiro (2015) stated that the protective effects of MET are attenuated by the pharmacological inhibition of AMPK or its absence [24]. MET can also inhibit mTORC1 via Rag GTPase, regardless of the activation of AMPK [47]. MTOR inhibition decreases protein synthesis and growth, inducing cell cycle arrest and apoptosis [25].
There is a hypothesis that the activation of AMPK can also confer resistance against cancer, as it was observed in cells without LKB1 of lung adenocarcinoma, after restoration of AMPK [24, 47]. Pecinovaet al. (2017) approached that the viability of cancer cells (rho0) without mitochondrial DNA is also affected by MET treatment, which makes the actions related to the respiratory chain questionable [50].