Antitumor potential of pacific plant extracts revealed using tumor spheroids and untargeted metabolomics.

BACKGROUND: The discovery of novel antitumor compounds remains a pressing need to address the global burden of cancer, particularly to fight treatment resistance and the lack of specificity of conventional therapies. The terrestrial flora from New Caledonia (NC), a biodiversity hotspot in the South Pacific, represents a rich and largely underexplored source of candidate antitumor natural products (NPs). PURPOSE: This study aimed to identify the most potent antitumor extracts among a selection of plants from the terrestrial flora of NC and to further characterize their pharmacological potential. METHODS: Ten extracts prepared from the leaves and bark of Alphitonia neocaledonica (Rhamnaceae), the aerial parts of Coleus forsteri (Lamiaceae), the bark of Scaevola taccada (Goodeniaceae), and the leaves and bark of Xylopia pancheri (Annonaceae) were evaluated across a panel of six tumor cell lines. Cytotoxic activity of identified hits was assessed against HCT116 colorectal carcinoma and Huh-7 hepatocarcinoma tumor spheroids, and selectivity was investigated ex vivo using peripheral blood mononuclear cells (PBMCs). Pharmacological interactions between the active extracts and conventional anticancer agents were subsequently evaluated. Metabolomic profiling of active extracts was performed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLCHRMS). RESULTS: Cyclohexane extracts of C. forsteri aerial parts and X. pancheri leaves exhibited cytotoxic activity against several tumor cell lines. Both extracts reduced the area and viability of HCT116 and Huh-7 tumor spheroids, while displaying moderate selectivity toward K562 chronic myeloid leukemia (CML) cells over ex vivo PBMCs. The active extracts displayed dose-dependent synergistic or antagonistic interactions with the conventional anticancer agents 5-fluorouracil (5-FU) and imatinib mesylate (IM). Principal component analysis (PCA) and heatmap visualization of UHPLCHRMS profiles revealed markedly distinct chemical signatures among the ten plant extracts, including between different plant parts of the same species. Partial least squares discriminant analysis (PLS-DA) based on the 30 most discriminating features further showed that the active extracts were enriched in features putatively annotated to abietane-type diterpenoids in C. forsteri and kaurene/trachylobane-type diterpenoids in X. pancheri. CONCLUSION: This study highlights the antitumor potential of NPs from the terrestrial flora of NC and provides novel evidence of the activity of selected plant extracts, including in physiologically relevant 3D tumor spheroid models. The enrichment of the most active extracts in abietane- and kaurene/trachylobane-type diterpenoids further points to these metabolite families as promising sources of novel anticancer agents.