Epidemiological studies have shown that metformin, a first line therapeutic agent for diabetes mellitus, reduced the risk of developing various malignancies. Several preclinical studies established some possible mechanisms of its anticancer effects. The primary effect of metformin action is a decrease in cell energy status, which activates AMP-activated kinase (AMPK), a cellular metabolic sensor. This event is followed by a decrease in serum concentrations of insulin and insulin growth factor I (IGF-I), the potent mitogens for cancer cells. In addition to the indirect mode of action, metformin may exhibit direct inhibitory effect on cancer cells by targeting mammalian target of rapamycin (mTOR) signaling and anabolic processes. This review gathers information on mechanisms of metformin antitumor activity, with special attention given to the impact of this antidiabetic drug on insulin/PI3K/mTOR and AMPK signaling. Furthermore, the factors required for this novel activity of metformin are discussed.

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Transforming growth factor β (TGF-β) is a multifunctional cytokine recognized as an important regulator of inflammatory responses. The effect of inositol hexaphosphate (IP6), a naturally occurring phytochemical, on the mRNA expression of TGF-β1, TGF-β2, TGF-β3 and TβRI, TβRII, and TβRIII receptors stimulated with bacterial lipopolysaccharides (Escherichia coli and Salmonella typhimurium) and IL-1β in intestinal cells Caco-2 for 3 and 12 h was investigated. Real-time qRT-PCR was used to validate mRNAs level of examined genes. Bacterial endotoxin promoted differential expression of TGF-βs and their receptors in a time-dependent manner. IL-1β upregulated mRNA levels of all TGF-βs and receptors at both 3 h and 12 h. IP6 elicited the opposed to LPS effect by increasing downregulated transcription of the examined genes and suppressing the expression of TGF-β1 at 12 h. IP6 counteracted the stimulatory effect of IL-1β on TGF-β1 and receptors expression by decreasing their mRNA levels. IP6 enhanced LPS- and IL-1β-stimulated mRNA expression of TGF-β2 and -β3. Based on these studies it may be concluded that IP6 present in the intestinal milieu may exert immunoregulatory effects and chemopreventive activity on colonic epithelium under inflammatory conditions or during microbe-induced infection/inflammation by modulating the expression of genes encoding TGF-βs and their receptors at transcriptional level.