Unveiling the multifaceted antiproliferative efficacy of <i>Cichorium endivia</i> root extract by dual modulation of apoptotic and inflammatory genes, inducing cell cycle arrest, and targeting COX-2

Abstract

Chicory (<i>Cichorium endivia</i> L. <i>divaricatum</i>) is a renowned medicinal plant traditionally used for various ailments, yet the pharmacological potential of its roots, particularly in terms of antitumor activity, remains elusive. In the present study, we explore, for the first time, the metabolomic profile of ethanolic extract from <i>Cichorium endivia</i> roots (CIR) and further unveil its antiproliferative potential. The untargeted phytochemical analysis UPLC/T-TOF-MS/MS identified 131 metabolites in the CIR extract, covering acids, amino acids, flavonoids, alkaloids, nucleotides, and carbohydrates. The antiproliferative activity of the CIR extract was tested in 14 cancer cell lines, revealing significant cytotoxicity (IC₅₀: 2.85-29.15 μg mL^-1) and a high selectivity index. Among the cells examined, the CIR extract recorded the most potent antiproliferative activity and selectivity toward HepG2 and Panc-1 cells, with an IC₅₀ of 2.85 μg mL^-1 and 3.86 μg mL^-1, respectively, and SI > 10. Insights into the mode of action of the antiproliferative activity revealed that CIR extract induces cell arrest in the S phase while diminishing cell distribution in the G0/G1 and G2/M phases in HepG-2 and Panc-1 cells. Flow cytometric and RT-PCR analysis revealed that the CIR extract significantly triggers apoptosis and modulates the expression of pro-apoptotic and anti-apoptotic genes. Furthermore, the CIR extract exhibited a pronounced anti-inflammatory activity, as evidenced by down-regulating key cytokines in LPS-induced RAW 264.7 cells and selectively inhibiting the COX-2 enzyme. Finally, the CIR extract showed a robust total antioxidant capacity, together with potent free radicals and metal scavenging properties, highlighting its role in alleviating oxidative stress. Taken together, this study highlights the multifaceted therapeutic potential of CIR extract as a natural-based antitumor supplement.