Dataset Information

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine.

ABSTRACT: A 1H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC50 value, were investigated, with respect to the controls (K), by the 1H-NMR of cells lysates and multivariate analysis (MVA) of the spectroscopic data. Relevant differences were found in the metabolic profiles of the different treatments with respect to the controls. A large overlap of the metabolic profiles in DT-8 vs. K and VIN vs. K suggests a similar biological response and mechanism of action, significantly diverse with respect to CDDP. On the other hand, DT8 seems to act by disorganizing the mitotic spindle and ultimately blocking the cell division, through a mechanism implying methionine depletion and/or S-adenosylmethionine (SAM) limitation.

SUBMITTER: Del Coco L

PROVIDER: S-EPMC7435671 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine.

Del Coco Laura L Majellaro Maria M Boccarelli Angelina A Cellamare Saverio S Altomare Cosimo Damiano CD Fanizzi Francesco Paolo FP

Molecules (Basel, Switzerland) 20200731 15

A <sup>1</sup>H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC<sub>50</sub> value, were investigated, with respect t ...[more]

PMID: 32752035

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Project description:BackgroundGriseofulvin, an antifungal drug, has recently been shown to inhibit proliferation of various types of cancer cells and to inhibit tumor growth in athymic mice. Due to its low toxicity, griseofulvin has drawn considerable attention for its potential use in cancer chemotherapy. This work aims to understand how griseofulvin suppresses microtubule dynamics in living cells and sought to elucidate the antimitotic and antiproliferative action of the drug.MethodsThe effects of griseofulvin on the dynamics of individual microtubules in live MCF-7 cells were measured by confocal microscopy. Immunofluorescence microscopy, western blotting and flow cytometry were used to analyze the effects of griseofulvin on spindle microtubule organization, cell cycle progression and apoptosis. Further, interactions of purified tubulin with griseofulvin were studied in vitro by spectrophotometry and spectrofluorimetry. Docking analysis was performed using autodock4 and LigandFit module of Discovery Studio 2.1.ResultsGriseofulvin strongly suppressed the dynamic instability of individual microtubules in live MCF-7 cells by reducing the rate and extent of the growing and shortening phases. At or near half-maximal proliferation inhibitory concentration, griseofulvin dampened the dynamicity of microtubules in MCF-7 cells without significantly disrupting the microtubule network. Griseofulvin-induced mitotic arrest was associated with several mitotic abnormalities like misaligned chromosomes, multipolar spindles, misegregated chromosomes resulting in cells containing fragmented nuclei. These fragmented nuclei were found to contain increased concentration of p53. Using both computational and experimental approaches, we provided evidence suggesting that griseofulvin binds to tubulin in two different sites; one site overlaps with the paclitaxel binding site while the second site is located at the alphabeta intra-dimer interface. In combination studies, griseofulvin and vinblastine were found to exert synergistic effects against MCF-7 cell proliferation.ConclusionsThe study provided evidence suggesting that griseofulvin shares its binding site in tubulin with paclitaxel and kinetically suppresses microtubule dynamics in a similar manner. The results revealed the antimitotic mechanism of action of griseofulvin and provided evidence suggesting that griseofulvin alone and/or in combination with vinblastine may have promising role in breast cancer chemotherapy.

Project description:In the context of the Human Toxome project, mass spectroscopy-based metabolomics characterization of estrogen-stimulated MCF-7 cells was studied in order to support the untargeted deduction of pathways of toxicity. A targeted and untargeted approach using overrepresentation analysis (ORA), quantitative enrichment analysis (QEA) and pathway analysis (PA) and a metabolite network approach were compared. Any untargeted approach necessarily has some noise in the data owing to artifacts, outliers and misidentified metabolites. Depending on the chemical analytical choices (sample extraction, chromatography, instrument and settings, etc.), only a partial representation of all metabolites will be achieved, biased by both the analytical methods and the database used to identify the metabolites. Here, we show on the one hand that using a data analysis approach based exclusively on pathway annotations has the potential to miss much that is of interest and, in the case of misidentified metabolites, can produce perturbed pathways that are statistically significant yet uninformative for the biological sample at hand. On the other hand, a targeted approach, by narrowing its focus and minimizing (but not eliminating) misidentifications, renders the likelihood of a spurious pathway much smaller, but the limited number of metabolites also makes statistical significance harder to achieve. To avoid an analysis dependent on pathways, we built a de novo network using all metabolites that were different at 24 h with and without estrogen with a p value <0.01 (53) in the STITCH database, which links metabolites based on known reactions in the main metabolic network pathways but also based on experimental evidence and text mining. The resulting network contained a "connected component" of 43 metabolites and helped identify non-endogenous metabolites as well as pathways not visible by annotation-based approaches. Moreover, the most highly connected metabolites (energy metabolites such as pyruvate and alpha-ketoglutarate, as well as amino acids) showed only a modest change between proliferation with and without estrogen. Here, we demonstrate that estrogen has subtle but potentially phenotypically important alterations in the acyl-carnitine fatty acids, acetyl-putrescine and succinoadenosine, in addition to likely subtle changes in key energy metabolites that, however, could not be verified consistently given the technical limitations of this approach. Finally, we show that a network-based approach combined with text mining identifies pathways that would otherwise neither be considered statistically significant on their own nor be identified via ORA, QEA, or PA.

Dataset Information

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine.

Publications

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine.

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