| Summary: | This study presents a comparison between two mistletoe plants—<i>P. acacia</i> and <i>P. curviflorus</i>—regarding their total phenolic contents and antioxidant and anticancer activities. <i>P. curviflorus</i> exhibited a higher total phenolics content (340.62 ± 19.46 mg GAE/g extract), and demonstrated higher DPPH free radical scavenging activity (IC<sub>50</sub> = 48.28 ± 3.41µg/mL), stronger reducing power (1.43 ± 0.54 mMol Fe<sup>+2</sup>/g) for ferric ions, and a greater total antioxidant capacity (41.89 ± 3.15 mg GAE/g) compared to <i>P. acacia</i>. The cytotoxic effects of <i>P. acacia</i> and <i>P. curviflorus</i> methanol extracts were examined on lung (A549), prostate (PC-3), ovarian (A2780) and breast (MDA-MB-231) cancer cells. The highest anticancer potential for the two extracts was observed on PC-3 prostate cancer cells, where <i>P. curviflorus</i> exhibited more pronounced antiproliferative activity (IC<sub>50</sub> = 25.83 μg/mL) than <i>P. acacia</i> (IC<sub>50</sub> = 34.12 μg/mL). In addition, both of the tested extracts arrested the cell cycle at the Pre-G1 and G1 phases, and induced apoptosis. However, <i>P. curviflorus</i> extract possessed the highest apoptotic effect, mediated by the upregulation of p53, Bax, and caspase-3, 8 and 9, and the downregulation of Bcl-2 expression. In the pursuit to link the chemical diversity of <i>P. curviflorus</i> with the exhibited bioactivities, its metabolomic profiling was achieved by the LC-ESI-TOF-MS/MS technique. This permitted the tentative identification of several phenolics—chiefly flavonoid derivatives, beside some triterpenes and sterols—in the <i>P. curviflorus</i> extract. Furthermore, all of the metabolites in <i>P. curviflorus</i> and <i>P. acacia</i> were inspected for their binding modes towards both CDK-2 and EGFR proteins using molecular docking studies in an attempt to understand the superiority of <i>P. curviflorus</i> over <i>P. acacia</i> regarding their antiproliferative effect on PC-3 cancer cells. Docking studies supported our experimental results; with all of this taken together, <i>P. curviflorus</i> could be regarded as a potential prospect for the development of chemotherapeutics for prostate cancer.
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