Investigação dos potenciais anti-inflamatório e antitumoral de análogos do resveratrol

Abstract

Resveratrol is a polyphenolic phytoalexin stilbene produced by many plants in response to hostile environmental conditions, recognized to present innumerous biological activities, such as antioxidant, anti-inflammatory, analgesic, antiviral, cardioprotective, antitumor and others. However, the reduced bioavailability of resveratrol has been the limiting factor for its widespread use. Therefore, chemically modified resveratrol analogs that have its activities potentiated, eliminating the problem of bioavailability, are the subject of investigations. Thus, the aim of the present study was to evaluate the anti-inflammatory and antitumor potential of resveratrol analogues. Fifteen analogues were evaluated for physicochemical properties and influence on the viability of RAW 264.7 cells and 4T1 strain tumor cells (MTT method), determining the analogs with highest potential to remain in the study. Thus, the eight selected analogs were tested on another cell line (J774.A1) and a primary culture (peritoneal macrophages), confirming their innocuity to it. These analogs also had LC50 determined on RAW 264.7 cells. Next, it was tested for antioxidant potential (DPPH ion capture assay); evaluated on the influence on the production of nitric oxide (NO) (Griess reaction for nitrite dosing); cytokines (IL-1, IL-6, IL-10, IL-12, IFN- and TNF-α) and chemokine (MCP1) (both by Elisa); Expression of MHCII and CD80, CD86 and CTLA-4 (flow cytometry) and proliferation of T and B lymphocytes (MTT method). From these data, four analogs used topically in a model of acute inflammation of ear edema were found, revealing satisfactory results for all analogues. However, two of them excelled and were employed in a Zymosan-induced arthritis model, confirming that they are able to provide results comparable to dexamethasone. As for the direct antitumor potential of synthetic molecules, the LC50 and the selectivity index (SI) against human breast cancer cells (MCF-7) and murine (4T1) and murine melanoma (B16) were determined. The obtained results revealed that at least five analogs can be exploited in this way, presenting comparable or higher SI than drugs classically used in antineoplastic therapy. Further studies shall be conduct in order to determine the mechanisms of action involved in anti-inflammatory activity, the influence of immunomodulation on antitumor activity and the bioavailability of these analogs.