Chemical composition, antiproliferative, and cell death potential of crude and digested jabuticaba (Myrciaria cauliflora) leaf extracts in HepG2 human hepatocellular carcinoma cells in 2D and 3D culture: a bioprospecting approach

Hepatocellular carcinoma is the most common primary liver tumor and continues to contribute significantly to cancer deaths. Jabuticaba leaves have been described as an excellent source of bioactive compounds, which have been shown to exert promising modulatory and functional effects on the carcinogenesis process. The present study aimed to evaluate the phenolic composition and the effects of crude extracts and digested fractions of jabuticaba tree leaf on the proliferative behavior of hepatocellular carcinoma (HepG2) cells, cultured in a two-dimensional monoculture (2D) and HepG2 cell multicellular tumor spheroids (3D). Quercetin 3-glucoside, gallic acid, isorhamnetin, naringin, and 4-hydroxybenzoic acid were the main compounds identified in the crude extract, while 3,4-dihydroxybenzoic acid and ferulic acid were detected only in the digested fractions. In monoculture assays, both the extract and the digested fractions exhibited cytotoxic and antiproliferative effects on HepG2 cells, inducing apoptotic and necrotic cell death, inhibiting cell migration, and showing antioxidant activity against reactive oxygen species (ROS) generation. In the 3D culture, the gastric fraction showed the highest activity, reducing cell viability by 40 % at a concentration of 200 μg GAE/mL. Moreover, the treatments altered the spheroid area and diameter measurements. Our findings indicate that the analyzed extracts constitute a valuable source of bioactive compounds, which exhibit modulatory effects on HepG2 cells and possess potential applications as nutraceuticals. In addition, we report for the first time the impact of jabuticaba leaf extracts in a 3D culture.