The Anticancer Effect of a Flavonoid-Rich Extract of Bergamot Juice in THP-1 Cells Engages the SIRT2/AKT/p53 Pathway

Abstract

Novel targets are constantly sought to fight hematologic malignancies. In this regard, high levels of SIRT2 expression are associated with unfavorable prognosis of acute myeloid leukemia. The interest in the plant kingdom has allowed the identification of ever-new anti-leukemic agents. Citrus × bergamia (bergamot) was proved to possess anticancer properties, yet no evidence is available regarding leukemia. For the first time, we studied the potential anti-leukemic effect of a flavonoid-rich extract of bergamot juice (BJe) in THP-1 cells, investigating the underlying mechanisms. Our findings showed that BJe reduced THP-1 cell proliferation, without affecting that of primary PBMCs, blocking the cell cycle in S phase and inducing apoptosis. Triggering of both extrinsic and intrinsic apoptotic pathways was witnessed by cleavage of caspase-8 and -9, which in turn activated caspase-3 and PARP. Interestingly, the increased p53 acetylation in THP-1 cells underlies SIRT2 inhibition by BJe, that was proved also in the isolated enzyme. Moreover, BJe hampered SIRT2 also by lowering its gene expression. Finally, BJe reduced AKT phosphorylation, which we hypothesized being the joining link between SIRT2 and p53, that play a pivotal role in BJe-induced cell cycle arrest and apoptosis in THP-1 cells. Our results suggest BJe as a potential anti-leukemic agent, via targeting of the SIRT2/AKT/p53 pathway.

Bergamot Byproducts: A Sustainable Source to Counteract Inflammation

“…However, in a complex context like the tumor microenvironment, other factors come into play including the family of sirtuins. Interestingly, the antileukemic effects observed for BJe and some flavanones it contains on leukemic THP-1 cells were mediated by the inhibition of the SIRT2 enzyme [ 104 , 105 ]. Anticancer effects induced by bergamot derivatives were also observed in murine models [ 106 ].…”

NAD+-A Hub of Energy Metabolism in Heart Failure

“…Reduced activity of the sirtuin isoform, sirt2 deacetylase, contributes to PARP-mediated myocyte death. However, activation of this enzyme can prevent PARP-mediated NAD + depletion and subsequent cell injury 33 .…”

Valorization of Agro-Industrial Orange Peel By-Products through Fermentation Strategies

“…It is well known that Citrus by-products are a rich source of biologically active compounds, such as vitamins, dietary fiber, pectin, polyphenols and essential oils. These have positive health effects, including antioxidant [81], prebiotic [100], antimicrobial [101,102], anticancer [103], anti-inflammatory [104,105] and antidiabetic effects. Such features make these by-products usable in many biotechnological applications (health care, pharmaceuticals, cosmetics, food and textiles).…”