| Summary: | <i>Lantana camara</i> L. and <i>Lantana montevidensis</i> Briq. (F. Verbenaceae) are invasive ornamental weeds native to the tropical regions of Africa and America. The leaves of both species have been traditionally used as infusions for treating fever, rheumatism, and cancer. LC–MS–MS-guided profiling of the methanolic extracts of the leaves of <i>L. camara</i> and <i>L. montevidensis</i> growing in Egypt led to the putative identification of 59 compounds belonging to terpenoids, flavonoids, iridoid glycosides, phenolic acids, and their derivatives. The <i>in-vitro</i> antioxidants and anti-inflammatory and anticancer activities of the two extracts were investigated. <i>L. camara</i> and <i>L. montevidensis</i> inhibited DPPH<sup>•</sup> (IC<sub>50</sub> = 34.01 ± 1.32 and 47.43 ± 1.74 µg/mL), ABTS<sup>+</sup> (IC<sub>50</sub> = 30.73 ± 1.42 and 40.37 ± 1.51 µg/mL), and superoxide anion (IC<sub>50</sub> = 1.57 ± 0.19 and 1.31 ± 0.14 μg/mL) free radicals. A potent anti-inflammatory effect was observed for both species through the inhibition of elastase release in fMLF/CB-induced human neutrophils (IC<sub>50</sub> = 2.40 ± 0.16 and 1.90 ± 0.07 μg/mL). The extracts showed significant cytotoxic activity against a panel of cancer cell lines with the most potent activity against Caco cells (IC<sub>50</sub> = 45.65 ± 1.64 and 40.67 ± 1.52 µg/mL for <i>L. camara</i> and <i>L. montevidensis</i>, respectively). Western blotting supported by FACS analysis revealed that the extracts inhibited cancer cell proliferation, reduced metastasis, and induced apoptosis resulting in cell cycle arrest. This was achieved via increasing mRNA and protein expressions of p53 and GSK-3β as well as decreasing the expression of PI3K, Akt, and cyclin D1.
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