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Theses

Antitumoral actions of natural stilbenes derived from Vitis vinifera

Abstract : The main objective of this Doctoral Thesis is to study the potential anti-inflammatory and anti-tumor activity of resveratrol and other stilbenes present in Vitis vinifera. To achieve this goal, the anti-inflammatory effect of stilbenes is firstly addressed in a lipopolysaccharide (LPS) -activated murine macrophage model, and secondly, antitumor activity in a model of human hepatocarcinoma is analyzed.The stilbenes used for the analysis of antitumor activity comprise 8 monomers (resveratrol, piceide, piceatannol, astringin A, pterostilbene, oxyresveratrol, isorhapontine and isorhapontigenine), 7 dimers (e-viniferin, w-viniferin, d-viniferin, ampelopsin A escirpusin A, pallidol and vitisinol C), a trimer (miyabenol C) and 4 tetramers (hopeaphenol, isohopeaphenol, R2-viniferin and R-viniferin). All were tested in the LPS-activated murine macrophage line, analyzing both their cytotoxicity and their ability to inhibit NO production. From these experiments, their IC30 or IC50, respectively, were calculated. The stilbenes selected based on the results obtained were piceatanol, e-viniferin, δ-viniferin, hopeaphenol and isohopeaphenol, with which the effect that they exert on the release of inflammatory cytokines and the production of ROS was studied. Hopeaphenol and piceatannol inhibit ROS production, and only δ-viniferin does not decrease the release of cytokines IL-1β and TNF-α. It is concluded that the derivatives of resveratrol piceatanol, -viniferin, hopeaphenol and isohopeaphenol have interesting effects on the inflammatory response produced by the activation that LPS exerts on murine macrophages. This finding justifies continuing the study in more complex models given its possible usefulness in the treatment of diseases with an inflammatory basis.For the study of antitumor activity, the IC50 obtained after treatment with 6 stilbenes from the 2 hepatoma lines were compared with the line of non-transformed hepatocytes. Resveratrol (monomer), ampelopsin A and e-viniferin (dimers) and the tetramers hopeaphenol, isohopeaphenol, R2-viniferin and R-viniferin were analyzed. The R2-viniferin tetramer shows the highest cytotoxic activity in HepG2 (IC50 <10 µM), without being toxic at this concentration for HH4. Hep3B cells are notably more resistant to R2-viniferin (IC50 48 µM). Stilbene produced increased HepG2 cells in SubG0, without alteration in Hep3B. The different response to this stilbene turned out to be due to the different status of p53, since silencing p53 in HepG2 cells increased their resistance to treatment, while transfection of p53 into Hep3B made them more sensitive. R2-viniferin causes phosphorylation of p53 in HepG2.The activation of caspase 3 and 9, the increase in the ratio of Bax / Bcl2 proteins and the release of intracellular LDH evidenced cell death by apoptosis and necrosis caused by that stilbene, which can be modulated by the PI3K/Akt and ERK1/2 on HepG2. Furthermore, the expression of histone ɣ-H2AX showed the damage that treatment with R2-viniferin produces in DNA. The key role that free radicals play in this entire process was elucidated due to the increased production of ROS and H2O2 and the increase in Mn-SOD activity. It was also shown that R2-viniferin decreases the migration and colony formation capacity of HepG2.It is concluded that the R2-viniferin tetramer exerts its anti-tumor activity through apoptosis mechanisms linked to p53 and is a promising compound with potential effects for chemoprevention and treatment of liver cancer.
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Submitted on : Thursday, January 21, 2021 - 3:09:18 PM
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Iris Aja Perez. Antitumoral actions of natural stilbenes derived from Vitis vinifera. Cellular Biology. Université de Bordeaux; Universidad del País Vasco. Facultad de ciencias, 2020. English. ⟨NNT : 2020BORD0115⟩. ⟨tel-03117766⟩

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