Time-Resolved Metabolomics Reveals Distinct, Cell- and Variety-Dependent Profiles of Prostanoids in Melanoma Cells Exposed to Fruit Extracts from Cornus mas and C. officinalis: A Pilot Study.

Chronic inflammation and cyclooxygenase (COX)-2-mediated prostanoid signaling contribute to melanoma progression, yet their modulation by natural products remains poorly defined. We examined the effects of dogwood fruit extracts-Japanese cornel (Cornus officinalis) and two European cultivars ('Uholok', 'Yantarnyi')-on temporal prostanoid dynamics in A375 (primary tumor-derived) and MeWo (metastasis-derived) mela-noma cells. Dynamic changes rather than static levels were modeled using GAMLSS or zero-inflated Gamma models to assess time, cell line, cornel type, and dose effects. Untreated A375 cells showed time-dependent increases in PGE2, PGF2α, thromboxane B2, and 13,14-dihydro-PGE1, consistent with inducible COX-2 activation, whereas MeWo cells maintained consistently high prostanoid levels, reflecting constitutive COX-2 expression. Cornus extracts modulated these trajectories in a cell- and dose-dependent manner. In A375, low concentrations allowed prostanoid accumulation, while higher doses flattened or reversed these increases; Japanese cornel produced the strongest inhibition, whereas European cultivars showed weaker or cultivar-specific effects. MeWo cells were less responsive, with significant changes emerging only at higher doses. PGD2 and 6-keto-PGF1α remained largely unchanged, indicating selective targeting of COX-2-dependent prostanoids. Extracts also reduced accumulation of downstream prostanoids, including 15-deoxy-Δ12,14-PGJ2 and 13,14-dihydro-PGE1, particularly in A375 cells. These differences highlight a stronger susceptibility of early-stage melanoma to phytochemical intervention and support cultivar-dependent bioactivity linked to phytochemical composition. In summary, Cornus extracts selectively attenuate time-dependent trajectories of tumor-promoting prostanoids-most effectively with Japanese cornel-while sparing homeostatic mediators, warranting further investigation on their potential for melanoma chemoprevention or adjunctive therapy.