Biological and metabolomics-guided isolation of tetrahydrofurofuran lignan from Croton spp. with antiproliferative activity against human melanoma cell line.

The Croton genus (Euphorbiaceae) is recognized as a promising source for identifying bioactive compounds with antiproliferative activity. However, knowledge on the chemical composition and activity of Croton floribundus, Croton echinocarpus, and Croton zehntneri is limited. Thus, this study aimed to investigate the antiproliferative activity of these species on cells derived from tumoral breast, lung, and melanoma cells, and primary fibroblasts derived from human skin. Metabolomic strategies were applied via ultra-performance liquid chromatography coupled with high-resolution mass spectrometry and multivariate statistical analysis to target the main active compound. The C. floribundus leaf extract exhibited the highest activity, with an IC50 value lower than that of the reference drug - temozolomide - in the most responsive cell line - SK-MEL-147 - and in all the evaluated melanoma cell lines (SK-MEL-147, CHL-1 and WM-1366). Four tetrahydrofurofuran lignans were isolated for the first time from the most promising fraction of the C. floribundus extract. According to the metabolomic and multivariate statistical analyses, the isolated lignan epi-yangambin constituted the main antiproliferative compound against SK-MEL-147; furthermore, it exhibited selective antiproliferative activity for this cell line (IC50 = 13.09 µg/mL and selectivity index = 3.82; temozolomide, IC50 = 121.50 µg/mL) due to, at least in part, its ability to inhibit cell cycle progression at G2/M. This is especially relevant considering the high resistance of melanoma cells to available drugs. Thus, epi-yangambin can serve as a prototype for further antiproliferative investigations.

Antiproliferative potential of essential oil from the leaves of Croton floribundus (Euphorbiaceae) against human metastatic melanoma cell lines.

Melanoma is a cancer type with high lethality, metastatic capacity, and limited therapeutic options. Different essential oils have been reported with antitumoral potential.  Thus, the essential oil (EO) of the leaves of C. floribundus was obtained by hydrodistillation and analyzed by GC-MS. The majority of substances annotated were ß-selinene, E-Caryophyllene, and Premnaspirodiene. The cytotoxic activity of EO was evaluated on three melanoma cell lines SKMEL-147, WM-1366, and CHL-1, which are representative of metastatic melanoma with different mutation profiles. The IC50 values found for EO were lower than temozolomide (reference drug) in all melanoma cell lines. In addition, the selectivity of EO was upward when compared to the reference drug. Interestingly, the WM-1366 cell line was the most responsive, and these findings are very promising considering that it has shown high resistance to the plethora of compounds. Thus,  the C. floribundus EO is a promising source to drive further studies for the development of new treatments for metastatic melanoma, which is urgently relevant given the resistance of this pathology to current treatments.