Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by1H-decoupled-31P magnetic resonance spectroscopy

Manickam Muruganandham, Alan A. Alfieri, Cornelia Matei, Yuchun Chen, George Sukenick, Isabel Schemainda, Max Hasmann, Leonard B. Saltz, Jason A. Koutcher

Research output: Contribution to journalArticle

81 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3503-3513
Number of pages11
JournalClinical Cancer Research
Volume11
Issue number9
DOIs
StatePublished - May 1 2005
Externally publishedYes

Fingerprint

NAD
Magnetic Resonance Spectroscopy
Apoptosis
Breast Neoplasms
Neoplasms
Radiation Tolerance
Cell Death
Metabolome
Glycolysis
Growth
Heterografts
Phosphorus
Energy Metabolism
Phospholipids
Histology
Leukemia
Research Design
Nucleotides
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by1H-decoupled-31P magnetic resonance spectroscopy. / Muruganandham, Manickam; Alfieri, Alan A.; Matei, Cornelia; Chen, Yuchun; Sukenick, George; Schemainda, Isabel; Hasmann, Max; Saltz, Leonard B.; Koutcher, Jason A.

In: Clinical Cancer Research, Vol. 11, No. 9, 01.05.2005, p. 3503-3513.

Research output: Contribution to journalArticle

Muruganandham, M, Alfieri, AA, Matei, C, Chen, Y, Sukenick, G, Schemainda, I, Hasmann, M, Saltz, LB & Koutcher, JA 2005, 'Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by1H-decoupled-31P magnetic resonance spectroscopy', Clinical Cancer Research, vol. 11, no. 9, pp. 3503-3513. https://doi.org/10.1158/1078-0432.CCR-04-1399
Muruganandham, Manickam ; Alfieri, Alan A. ; Matei, Cornelia ; Chen, Yuchun ; Sukenick, George ; Schemainda, Isabel ; Hasmann, Max ; Saltz, Leonard B. ; Koutcher, Jason A. / Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by1H-decoupled-31P magnetic resonance spectroscopy. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 9. pp. 3503-3513.
@article{b855dbd9ecb9472a9dc9400af468d941,
title = "Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by1H-decoupled-31P 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.",
author = "Manickam Muruganandham and Alfieri, {Alan A.} and Cornelia Matei and Yuchun Chen and George Sukenick and Isabel Schemainda and Max Hasmann and Saltz, {Leonard B.} and Koutcher, {Jason A.}",
year = "2005",
month = "5",
day = "1",
doi = "10.1158/1078-0432.CCR-04-1399",
language = "English (US)",
volume = "11",
pages = "3503--3513",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by1H-decoupled-31P magnetic resonance spectroscopy

AU - Muruganandham, Manickam

AU - Alfieri, Alan A.

AU - Matei, Cornelia

AU - Chen, Yuchun

AU - Sukenick, George

AU - Schemainda, Isabel

AU - Hasmann, Max

AU - Saltz, Leonard B.

AU - Koutcher, Jason A.

PY - 2005/5/1

Y1 - 2005/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=18244376911&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18244376911&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-04-1399

DO - 10.1158/1078-0432.CCR-04-1399

M3 - Article

VL - 11

SP - 3503

EP - 3513

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -