Marine plants and animals are sources of a huge number of pharmacologically active compounds, some of which exhibit
antineoplastic activity of clinical relevance. However the mechanism of action of marine natural products (MNPs) is poorly understood. In this study,
proton NMR spectroscopy-based metabolomics was applied to unravel biochemical disorders induced in human MCF7
breast cancer cells by 3 lead candidate anticancer MNPs:
ascididemin (Asc),
lamellarin-D (
Lam-D), and
kahalalide F (KF). Asc,
Lam-D, and KF provoked a severe decrease in
DNA content in MCF7 cells after 24-h treatment. Asc and
Lam-D provoked apoptosis, whereas KF induced non-apoptotic cell death. Metabolite profiling revealed major biochemical disorders following treatment. The response of MCF7
tumor cells to Asc involved the accumulation of
citrate (x17 the control level, P<0.001), testifying
enzyme blockade in
citrate metabolism, and the accumulation of
gluconate (x9.8, P<0.005), a metabolite never reported at such concentration in
tumor cells, probably testifying glycolysis shutdown. The response to
Lam-D involved the accumulation of
aspartate (x7.2, P<0.05),
glutamate (x14.7, P<0.05), and
lactate (x2.3, P<0.05), probably in relation with the targeting of the
malate-
aspartate shuttle, as discussed. The response to KF involved increased
lipid accumulation (
polyunsaturated fatty acids x9.8, P<0.05), and
phospholipid and
acetate derivative alterations. Altogether, this study demonstrates the potential of
proton NMR spectroscopy-based metabolomics to help uncover metabolic targets and elucidate the mechanism of cytotoxicity of candidate
antineoplastic MNPs.