Avaliação do efeito antitumoral e anticarcinogênico de análogos de simplificação estrutural da curcumina em modelos de câncer de pulmão humano

Abstract

Lung cancer is one of the leading causes of mortality worldwide, making the search for new, more selective and effective therapeutic agents essential. Curcumin, a polyphenol extracted from Curcuma longa, exhibits antitumor properties, but its low bioavailability limits its clinical use. In this study, curcumin analogs were synthesized and evaluated for their antiproliferative activity in human lung cancer cells (A549 and H460) and their selectivity toward healthy cells (PBMCs). The compounds were tested at increasing concentrations (0.190–200 μM), and IC₅₀ values were determined using the MTT assay. Analogs 8, 11, and 12 showed higher antiproliferative potency, with up to a 25-fold increase compared to the precursor compounds. Furthermore, cell cycle analysis revealed that these compounds induced arrest in the G2/M phase, suggesting inhibition of CDKs and cyclins. Flow cytometry-based cell death analysis indicated that analog 12 induced apoptosis, with a significant increase in cells in the sub-G0/G1 phase. Molecular docking studies revealed compound affinity for molecular targets associated with tumor progression, such as p53, KIT, EGFR, STAT3, and Bcl -2, corroborating the in vitro phenotypic data. Morphological analysis and wound healing assays were also conducted in the presence of TGF-β, demonstrating that the curcuminoids can attenuate the epithelial–mesenchymal transition process, especially when combined with inhibition of the TGF-β pathway. The in silico evaluation of ADME parameters indicated that the compounds possess good intestinal absorption and favorable physicochemical properties, although adjustments are needed to improve their oral bioavailability. Notably, analogs 11 and 12 showed high selectivity for tumor cells compared to PBMCs, suggesting a safer profile for future therapeutic applications. The results of this study indicate that structurally modified curcumin analogs exhibit enhanced antiproliferative activity, promote cell cycle arrest, and induce apoptosis in lung cancer cells, with lower toxicity toward healthy cells. Thus, these compounds emerge as potential candidates for the development of new chemotherapeutic agents, although further studies are necessary to validate their efficacy and safety.