Quantitative HRMAS proton total correlation spectroscopy applied to cultured melanoma cells treated by chloroethyl nitrosourea: Demonstration of phospholipid metabolism alterations

Morvan, Daniel; Demidem, Aïcha; Papon, Janine; Madelmont, J. C.

doi:10.1002/mrm.10368

Cited by 56 publications

(58 citation statements)

References 24 publications

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“…PUF accumulation may result from hydrolysis of membranes [28], inhibition of PUF consumption, or inhibition of cyclooxygenase-2 (COX-2) activity [29]. Actually, taxanes have been shown to yield mobile lipid formation [28,30] and variations of phospholipid metabolism derivatives [31], although not specifically among antineoplastic agents [28,[32][33][34]. PUF levels may relate an autophagic process implicating damaged membranes [30].…”

Section: Discussionmentioning

confidence: 99%

Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

Bayet-Robert

Morvan

Chollet

et al. 2009

Breast Cancer Res Treat

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There is growing evidence that docetaxel, a microtubule-targeting agent like the other taxane paclitaxel, induces dual cytotoxicity mechanism according to dose level. Postgenomics screening technologies are now more and more applied to the elucidation of drug response mechanisms. Proton nuclear magnetic resonance spectroscopy-based pharmacometabolomics was here applied to get further insight into the response of human MCF7 breast carcinoma cells to docetaxel at high (clinical, 5 lM) and low (1 nM) doses. The global response to both doses was evaluated by nuclear morphology and DNA content, the latter as an index of cell proliferation and DNA ploidy. High dose provoked long-lasting cell cycle arrest in mitosis during the first 48 h of exposure to treatment and severe decrease in DNA content followed by significant amount of cell death. In contrast, at low dose, no long-lasting cell cycle arrest was observed on micrographies, and DNA content was decreased but less than at high dose (P \ 0.05), without significant cell death. This response was compared to biochemical alteration assessed by pharmacometabolomics. Thirty metabolites were identified and quantified. Metabolite profiling at clinical dose revealed time-dependent disorders in derivatives of glycolysis, lipid metabolism and glutathione metabolism.Comparison between high and low doses was performed at 72 h and showed common traits including the accumulation of cytidinediphosphocholine (95.0 and 96.9, respectively, P \ 0.03), the decrease in phosphatidylcholine (90.3 and 90.2, respectively, P \ 0.03), and gluthathione (90.6 and 90.6, respectively, P \ 0.03). Despite that, significant dosedependent differences were found in 12 of 30 measured metabolites. Among them, the most discriminant metabolites were polyunsaturated fatty acids (ratio of high-to-low dose of 14.8, P \ 0.05), glutamate, myoinositol, and homocysteine (ratio \ 0.4, P \ 0.05). In addition, the mechanism for glutathione decrease was different. At high dose, it resulted from extensive consumption with precursor starvation (glutamate: -89%, P \ 0.05) and increased glutathione S-transferase activity (95, P \ 0.01), whereas at low dose, it resulted from glutathione biosynthesis blockade with homocysteine accumulation (?144%, P \ 0.03) and decreased glutathione S-transferase activity (-70%, P \ 0.01). Altogether, this pharmacometabolomics analysis provides further evidence of the varying cellular responses at high and low doses of docetaxel in MCF7 breast cancer cells. The authors Mathilde Bayet-Robert and Daniel Morvan equally contributed to this work.

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Section: Discussionmentioning

confidence: 99%

Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

Bayet-Robert

Morvan

Chollet

et al. 2009

Breast Cancer Res Treat

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“…Quantification was performed on an O2 workstation (Silicongraphics) using the built-in deconvolution software (XWIN-NMR v2.6, Bruker), and normalization was performed relative to the water signal as already reported. 22 Measured derivatives included phosphoethanolamine (PE) (CH 2 signal at 3.99 ppm), phosphatidylcholine (PtdCho) (N(CH 3 ) 3 broad signal at 3.26 ppm), taurine (Tau) (CH 2 signal at 3.43 ppm), glycine (Gly) (CH 2 signal at 3.56 ppm), lysine (Lys) (e-CH 2 signal at 3.00 ppm), total creatine (tCr) (CH 2 signal at 3.93 ppm), lactate (Lac) (CH 3 signal at 1.33 ppm), alanine (Ala) (CH 3 signal at 1.47 ppm). Also total glutathione (GSx 5 reduced 1 oxidized glutathione) (CH 2 signal at 2.55 ppm) was quantified.…”

Section: Proton High Resolution Magic Angle Spinning Nmr Spectroscopymentioning

confidence: 99%

Bystander effects are induced by CENU treatment and associated with altered protein secretory activity of treated tumor cells A relay for chemotherapy?

Demidem

Morvan

Madelmont

2006

Intl Journal of Cancer

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In a previous study, it was reported that secondary untreated melanoma tumors implanted several weeks after and at distance from primary chloroethylnitrosourea (CENU)-treated tumors underwent differentiation and growth inhibition. To see whether the primary treated tumor released soluble factors that mediated the secondary tumor response, serum transfer experiments were performed in vivo. Administration of serum from CENU-treated tumor-bearing donors arrested tumor proliferation, decreased vessel formation and induced tumor metabolite alterations encompassing glutathione decrease and polyunsaturated fatty acid and phosphoethanolamine increase. These changes mimicked secondary tumor phenotype. To reproduce the model in vitro, cell culture supernatant transfer experiments were performed. CENU-treated cell cultures showed polyploidy and reactive oxygen species (ROS) production. Cell cultures challenged by a conditioned medium of CENU-treated cells underwent growth inhibition, cytoskeleton disorders, cytokinesis retardation, metabolite alterations, glutathione decrease and phosphoethanolamine increase, without ROS elicitation. Proteomics of CENU-treated cell conditioned media revealed altered protein secretion activity by CENU-treated cells. Among de novo secreted proteins, the most expressed were phosphatidylethanolamine-binding protein (PEBP), cardiovascular heat shock protein (cHsp), Rho-associated coiled-coil forming kinase 2 (ROCK) and actin fragments. These proteins testified of cytoskeleton disorders, growth inhibition and metabolite alterations. This article demonstrates the release by CENU-treated tumors of growth inhibitory differentiation-inducing soluble factors. These factors mediate remote bystander effects and attest persistent biological activity of residual tumors after chemotherapy. ' 2006 Wiley-Liss, Inc.Key words: chloroethylnitrosoureas; distant double tumor models; growth inhibition; bystander effects; proteomics There is increasing experimental evidence that therapy-induced tumor cell modification (cell-based gene and ionizing radiation therapies) may promote the immune system or induce the expression of cytokines or other factors that may be inhibitory for local or distant unmodified tumor cells. [1][2][3][4][5][6][7][8] Cell-based gene therapy after cytokine or suicide gene transfer has been investigated for autologous and allogeneic vaccination in cancer therapy. Tumor cells engineered to produce cytokines such as interleukin-12 (IL-12) induced antitumor immunity capable of inhibiting a challenge with unmodified parental tumor cells.1 Recently, in a model of allogeneic tumor cells transduced with IL-12 mixed with autologous lymphoma cells, IL-12 induced microenvironmental changes that, through the induction of an immune response, yielded eradication of distant preestablished lymphoma.2 Cells transfected with a suicide gene such as that of thymidine kinase from herpes simplex virus 3-6 or of cytosine desaminase, 7-8 enzymes that activate a drug or prodrug, inhibited distant tumors and provok...

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“…We previously reported that B16 melanoma cells responded to chloroethylnitrosourea (CENU)-induced DNA damage (11), by G 2 /M cell cycle arrest, biopolar spindle blockade, glycolysis downregulation followed by adaptative and/or redifferentiation processes (12,13). This suggested the inhibition of the Akt/PKB pathway as a possible consequence of PP2A activation in response to DNA damage.…”

Section: Introductionmentioning

confidence: 99%

PP2A activity is controlled by methylation and regulates oncoprotein expression in melanoma cells: A mechanism which participates in growth inhibition induced by chloroethylnitrosourea treatment

Guenin

Schwartz²,

Morvan³

et al. 2008

Int J Oncol

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Abstract. Protein phosphatase 2A (PP2A), an Akt pathway inhibitor, is considered to be activated by methylation of its catalytic subunit. Also PP2A downregulation was proposed to take part in carcinogenesis. Recently, PP2A activation was shown to be activated in response to DNA damage. To obtain further information on the role of PP2A in tumors and response to DNA damage, we investigated the relationship between PP2A methylation and activity, cell proliferation, Akt activation, c-Myc expression and PTEN activity in B16 melanoma cells untreated and after chloroethylnitrosourea (CENU) treatment. In untreated cells, okadaic acid, an antagonist of PP2A methylation, inhibited PP2A activity, stimulated cell proliferation, increased Akt activation and c-Myc expression. Xylulose-5-phosphate, an agonist of PP2A methylation, increased PP2A activity, decreased cell proliferation, Akt activation and c-Myc expression. However, both PP2A methylation modulators increased PTEN activity. During the response to CENU treatment, PP2A methylation and activity were strongly increased, Akt activation and c-Myc expression were decreased. However PTEN activity was increased. After tumor cell growth recovery, these modifications were moderately decreased. PP2A methylation was quantified and correlated positively with PP2A activity, and negatively with criteria for cell aggressiveness (cell proliferation, Akt activation, c-Myc expression). Based on these data, PP2A methylation status controls PP2A activity and oncoproteins expression and PP2A is strongly activated after CENU treatment thus partly explaining the growth inhibition in response to this agent. It follows that PP2A promethylating agents are potential candidates for anticancer drugs.

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Quantitative HRMAS proton total correlation spectroscopy applied to cultured melanoma cells treated by chloroethyl nitrosourea: Demonstration of phospholipid metabolism alterations

Cited by 56 publications

References 24 publications

Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

Bystander effects are induced by CENU treatment and associated with altered protein secretory activity of treated tumor cells A relay for chemotherapy?

PP2A activity is controlled by methylation and regulates oncoprotein expression in melanoma cells: A mechanism which participates in growth inhibition induced by chloroethylnitrosourea treatment

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