Avaliação da atividade antitumoral de compostos análogos do resveratrol

Abstract

Resveratrol (RVT) is a natural phytoalexin synthesized by certain plant species in response to stress. Its main dietary sources include grapes, red wine, peanuts, and soy. Among the biological actions of this compound, its anti-tumor activity stands out as it affects various mediators involved in cancer initiation, promotion, and progression, along with apoptosis and cell cycle regulation. However, despite these important actions, RVT has low bioavailability in mammals, limiting its in vivo use. To overcome this barrier, a viable alternative is the construction of analog compounds with improved chemical structure and potential to maintain RVT's biological activities. Thus, the aim of this study was to evaluate the anti-tumor potential of six compounds (AR07, AR08, AR22, AR25, AR26, and AR33), RVT analogs, in a murine breast cancer model. Firstly, the compounds' influence on the viability of J774A.1 cells (murine macrophages) and 4T1 cells (murine mammary adenocarcinoma) was determined using the MTT method. Subsequently, the impact on 4T1 cell proliferation and migration was assessed through the MTT method and wound healing assay, respectively. The most promising analogs were evaluated in vivo in a murine mammary carcinoma model, where tumor growth and metastasis occurrence were analyzed. Following these assays, the most promising analog was selected, and its in vivo toxicity as well as its action after oral administration were determined. Finally, the mechanisms of action of this analog were investigated by evaluating the expression of CD39 and CD73 markers and the compound's ability to induce apoptosis and/or necrosis. The results demonstrated that AR26 and AR33 analogs exhibited better performance, with an acceptable impact on J774A.1 cell viability (viability above 70%) and reduced viability of 4T1 cells (25% and 70%, respectively). Moreover, in 4T1 cells, the compounds reduced proliferation (by approximately 50%) and inhibited wound area recovery by 50% and 80%, respectively. In the mammary carcinoma model, with intraperitoneal treatment, both compounds showed promising results by inhibiting tumor growth by 20% (AR26) and 43% (AR33), as well as reducing pulmonary (45% reduction for AR26 and 60% for AR33) and bone metastases (12% reduction for AR26 and 40% for AR33). Due to its superior performance, the AR33 compound underwent acute toxicity testing, demonstrating low toxicity at concentrations below 150mg/Kg. This compound also proved effective after oral administration, reducing tumor growth by approximately 50%, as well as the occurrence of lung metastases. Analysis of AR33 analog's mechanisms of action showed inhibition of CD73 marker expression. The results demonstrate that AR33 compound exhibits significant anti-tumor activity with potential to contribute to new therapeutic strategies against breast cancer.