Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by (1)H-decoupled-(31)P magnetic resonance spectroscopy Journal Article
| Authors: | Muruganandham, M.; Alfieri, A. A.; Matei, C.; Chen, Y.; Sukenick, G.; Schemainda, I.; Hasmann, M.; Saltz, L. B.; Koutcher, J. A. |
| Article Title: | Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by (1)H-decoupled-(31)P magnetic resonance spectroscopy |
| Abstract: | Purpose: Attempts to selectively initiate tumor cell death through inducible apoptotic pathways are increasingly being exploited as a potential anticancer strategy. Inhibition of NAD+ synthesis by a novel agent FK866 has been recently reported to induce apoptosis in human leukemia, hepatocarcinoma cells in vitro, and various types of tumor xenografts in vivo. In the present study, we used 1H-decoupled phosphorus ( 31P) magnetic resonance spectroscopy (MRS) to examine the metabolic changes associated with FK866 induced tumor cell death in a mouse mammary carcinoma. Experimental Design: Induction of apoptosis in FK866-treated tumors was confirmed by histology and cytofluorometric analysis. FK866-induced changes in mammary carcinoma tumor metabolism in vivo were investigated using 1H-decoupled 31P MRS. To discern further the changes in metabolic profiles of tumors observed in vivo, high-resolution in vitro 1H-decoupled 31P MRS studies were carried out with perchloric acid extracts of mammary carcinoma tumors excised after similar treatments. In addition, the effects of FK866 on mammary carcinoma tumor growth and radiation sensitivity were studied. Results: Treatment with FK866 induced a tumor growth delay and enhanced radiation sensitivity in mammary carcinoma tumors that was associated with significant increases in the 31P MR signal in the phosphomonoester region and a decrease in NAD+ levels, pH, and bioenergetic status. The 31P MRS of perchloric acid extracts of treated tumors identified the large unresolved signal in the phosphomonoester region as the resultant of resonances originating from intermediates of tumor glycolysis and guanylate synthesis in addition to alterations in pyridine nucleotide pools and phospholipid metabolism. Conclusion: The present results suggest that FK866 interferes with multiple biochemical pathways that contribute to the increased cell death (apoptosis) and subsequent radiation sensitivity observed in the mammary carcinoma that could be serially monitored by 31P MRS. © 2005 American Association for Cancer Research. |
| Keywords: | leukemia; unclassified drug; liver cell carcinoma; nonhuman; mitosis; animal cell; mouse; animals; mice; cell death; cell cycle; apoptosis; protein binding; tumor xenograft; drug effect; time factors; tumor cell line; magnetic resonance spectroscopy; nuclear magnetic resonance spectroscopy; radiosensitivity; piperidines; neoplasm transplantation; mitochondria; phosphorus nuclear magnetic resonance; glycolysis; nad; hydrogen-ion concentration; nicotinamide adenine dinucleotide; mammary neoplasms, experimental; phospholipids; mice, inbred c3h; pentosyltransferases; nadp; intracellular membranes; membrane potentials; annexin a5; fk 866; acrylamides; cytofluorometry; guanosine phosphate; nicotinamide adenine dinucleotide inhibitor; perchloric acid; guanine nucleotides |
| Journal Title: | Clinical Cancer Research |
| Volume: | 11 |
| Issue: | 9 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2005-05-01 |
| Start Page: | 3503 |
| End Page: | 3513 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-04-1399 |
| PUBMED: | 15867253 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 45" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus" |
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