Magnetic resonance spectroscopy for detection of choline kinase inhibition in the treatment of brain tumors.

Abstract

Abnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor progression. Increased choline is consistently observed in both preclinical tumor models and in human brain tumors by proton magnetic resonance spectroscopy (MRS). Thus, inhibition of choline metabolism using specific choline kinase inhibitors such as MN58b may be a promising new strategy for treatment of brain tumors. We demonstrate the efficacy of MN58b in suppressing phosphocholine production in three brain tumor cell lines. In vivo MRS studies of rats with intracranial F98-derived brain tumors showed a significant decrease in tumor total choline concentration after treatment with MN58b. High-resolution MRS of tissue extracts confirmed that this decrease was due to a significant reduction in phosphocholine. Concomitantly, a significant increase in poly-unsaturated lipid resonances was also observed in treated tumors, indicating apoptotic cell death. MRI-based volume measurements demonstrated a significant growth arrest in the MN58b-treated tumors in comparison with saline-treated controls. Histologically, MN58b-treated tumors showed decreased cell density, as well as increased apoptotic cells. These results suggest that inhibition of choline kinase can be used as an adjuvant to chemotherapy in the treatment of brain tumors and that decreases in total choline observed by MRS can be used as an effective pharmacodynamic biomarker of treatment response.

• Authors: Manoj Kumar, Sean P Arlauckas, Sona Saksena, Gaurav Verma, Ranjit Ittyerah, Stephen Pickup, Anatoliy V Popov, Edward J Delikatny, Harish Poptani
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 4 Pg. 899-908 (Apr 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25657334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• 1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide
• Antineoplastic Agents
• Butanes
• Enzyme Inhibitors
• Pyridinium Compounds
• Choline Kinase

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Brain Neoplasms (diagnosis, drug therapy, metabolism, pathology)
• Butanes (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Choline Kinase (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Female
• Humans
• Magnetic Resonance Imaging
• Magnetic Resonance Spectroscopy (methods)
• Proton Magnetic Resonance Spectroscopy
• Pyridinium Compounds (administration & dosage, pharmacology)
• Rats
• Xenograft Model Antitumor Assays