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].