| Summary: | Photochemotherapy is one of the most interesting current therapeutic approaches for the treatment of melanoma. Different classes of naturally occurring phytochemicals demonstrated interesting photoactive properties. The aim of this study was to evaluate the photocytotoxic potential of two <i>Cachrys</i> species from Southern Italy: <i>C. sicula</i> and <i>C. libanotis</i> (Apiaceae). The enriched-coumarin extracts were obtained from aerial parts through both traditional maceration and pressurized cyclic solid-liquid (PCSL) extraction using Naviglio extractor<sup>®</sup>. Qualitative and quantitative analyses of furanocoumarins were performed with GC-MS. The photocytotoxic effects were verified on C32 melanoma cells irradiated at a dose of 1.08 J/cm<sup>2</sup>. The apoptotic responses were also assessed. Moreover, phenolic content and the in vitro antioxidant potential were estimated. Xanthotoxin, bergapten, and isopimpinellin were identified. All the samples induced concentration-dependent photocytotoxic effects (IC<sub>50</sub> ranging from 3.16 to 18.18 μg/mL). The <i>C. libanoti</i>s sample obtained with Naviglio extractor<sup>®</sup> was the most effective one (IC<sub>50</sub> = 3.16 ± 0.21 μg/mL), followed by <i>C. sicula</i> sample obtained with the same technique (IC<sub>50</sub> = 8.83 ± 0.20 μg/mL). Both <i>Cachrys</i> samples obtained through PCSL induced up-regulation of apoptotic signals such as BAX (Bcl2-associated X protein) and PARP (poly ADP-ribose polymerase) cleavage. Moreover, these samples proved to be more photoactive, giving a greater upregulation of p21 protein in the presence of UVA radiation. Obtained results suggest that investigated species could be promising candidates for further investigations aimed to find new potential drugs for the photochemotherapy of skin cancer.
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