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Metabolic Signatures Associated with a NAD Synthesis Inhibitor–Induced Tumor Apoptosis Identified by ¹H-Decoupled-³¹P Magnetic Resonance Spectroscopy

Authors' Affiliations: Departments of ¹ Medical Physics, ² Radiology, ³ Medicine, and ⁴ Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York, and ⁵ Fujisawa GmbH, Munich, Germany

Requests for reprints: Jason A. Koutcher, Departments of Medical Physics and Radiology, Memorial Sloan-Kettering Cancer Center, 1275, York Avenue, New York, NY 10021. Phone: 212-639-8834; Fax: 212-717-3676; E-mail: koutchej{at}mskcc.org.

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.

Key Words: ³¹P NMR • Tumor • Metabolism • NAD • Apoptosis