Selective Cytotoxic and Antiproliferative Effects of Extracts from Four Mexican Medicinal Plants in Human Cancer and Non-Cancerous Cell Lines

<b>Background</b>: Medicinal plants used in traditional Mexican medicine represent a valuable source of bioactive compounds with potential anticancer activity. Beyond cytotoxic potency, selectivity toward cancer cells over normal cells is a critical toxicological parameter for identifying safer therapeutic candidates. This study aimed to evaluate the selective cytotoxic and antiproliferative effects of extracts from four Mexican medicinal plants across human cancerous and non-cancerous cell lines. <b>Methods</b>: Hexane, acetone, and methanolic extracts from <i>Semialarium mexicanum</i>, <i>Eryngium heterophyllum</i>, <i>Piper auritum</i>, and <i>Cochlospermum vitifolium</i> were evaluated in a panel of human cancer cell lines and non-tumoral models, including primary human uterine fibroblasts (HUFs). Cytotoxicity was assessed after 48 h of treatment using increasing extract concentrations, and selectivity indices were calculated. Cell cycle distribution and nuclear morphology analyses were performed to explore antiproliferative effects. Additionally, GC-MS-based chemical profiling was conducted on selected extracts to obtain a tentative characterization of major bioactive constituents. <b>Results</b>: The extracts exhibited differential cytotoxic profiles depending on plant species and solvent polarity. The hexane extract of <i>Semialarium mexicanum</i> showed the highest cytotoxic potency and selectivity toward cervical cancer cells, with half-maximal inhibitory concentration (<i>IC</i>₅₀); values of 15.9 ± 1.8 µg/mL and 17.2 ± 2.8 µg/mL in HeLa and SiHa cells, respectively, and selectivity index (SI) values > 5 when compared with primary human uterine fibroblasts (HUF). Extracts of <i>Eryngium heterophyllum</i> displayed moderate cytotoxic activity (<i>IC</i>₅₀ = 20-30 µg/mL in HeLa cells) with intermediate selectivity, whereas <i>Cochlospermum vitifolium</i> showed solvent-dependent effects and <i>Piper auritum</i> exhibited limited cytotoxicity. Cell cycle analysis revealed an increased sub-G1 population, and nuclear morphology assays demonstrated chromatin condensation and fragmentation in cancer cells, supporting an antiproliferative mechanism. GC-MS analysis of the hexane extract of <i>Semialarium mexicanum</i> suggested the presence of triterpenoid-related and other lipophilic compounds potentially associated with its selective anticancer activity. <b>Conclusions</b>: These findings provide in vitro evidence of selective anticancer activity of Mexican medicinal plant extracts and establish a basis for future mechanistic studies medicinal plant extracts and lay the groundwork for future mechanistic investigations.