Biochemical disorders induced by cytotoxic marine natural products in breast cancer cells as revealed by proton NMR spectroscopy-based metabolomics

Abstract

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.

Citrate induces apoptosis of the acute monocytic leukemia U937 cell line through regulation of HIF-1α signaling

“…It is well established that all cells survive of ATP supply and the fast growing cells require more energy supply to meet the biomass requirement of growth and proliferation, thus, it is possible that cancer cells are more sensitive to lack of energy, specifically lack of glucose. It is understandable that malignant cells are prone to death once energy supply is insufficient (8,36). In the current experiments, the AML U937, treated, with citrate was observed to exhibit an elevation in lactate production and an increase in pH value and thus, citrate exhibited a potent apoptotic inducing activity towards AML U937 cells while sparing the normal control cell.…”

Metabolomics as a Challenging Approach for Medicinal Chemistry and Personalized Medicine

“…171 Metabolic profiling studies on human oral squamous cell carcinoma using 1 H-NMR-based metabolomics was also successful for the identification of an extract from the leaves of Camptotheca acuminate as a possible source of the anticancer drug camptothecin. 172 While all of these studies mentioned above implemented NMR, a very recent study used mass spectrometry to reveal a sulfur-containing, angiotensin-converting enzyme inhibitor isolated from Asparagus officinalis.…”

The Future of NMR Metabolomics in Cancer Therapy: Towards Personalizing Treatment and Developing Targeted Drugs?

“…also evaluated the potential cytotoxic effects of three marine natural products (MNP) on MCF7 breast cancer cells [89]. All three products resulted in cell death, but presented a different mechanism of action.…”