title: 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: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Manoj
authors: M
authors: Kumar
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Sean P
authors: SP
authors: Arlauckas
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Sona
authors: S
authors: Saksena
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Gaurav
authors: G
authors: Verma
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Ranjit
authors: R
authors: Ittyerah
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Stephen
authors: S
authors: Pickup
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Anatoliy V
authors: AV
authors: Popov
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Edward J
authors: EJ
authors: Delikatny
authors: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Department of Cellular and Molecular Physiology, Institute of Regenerative Medicine, University of Liverpool, Liverpool, United Kingdom. harish.poptani@liverpool.ac.uk.
authors: Harish
authors: H
authors: Poptani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D002073:Butanes / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D066244:Proton Magnetic Resonance Spectroscopy; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: C507944:1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide; D000970:Antineoplastic Agents; D002073:Butanes; D004791:Enzyme Inhibitors; D011726:Pyridinium Compounds; D002797:Choline Kinase
references: Neuroimage. 2009 Apr 1;45(2):360-9
references: 19154791
references: Neurol Clin. 2007 Nov;25(4):947-73, viii
references: 17964022
references: Prog Lipid Res. 2004 May;43(3):266-81
references: 15003397
references: Oncogene. 2003 Dec 4;22(55):8803-12
references: 14654777
references: Lancet Oncol. 2007 Oct;8(10):889-97
references: 17851129
references: J Natl Cancer Inst. 1999 Aug 4;91(15):1281-7
references: 10433616
references: Cancer Res. 2004 Sep 15;64(18):6732-9
references: 15374991
references: NMR Biomed. 2011 Jul;24(6):592-611
references: 21538631
references: NMR Biomed. 2001 Jun;14(4):260-4
references: 11410943
references: Neuro Oncol. 2012 Aug;14(8):979-93
references: 22679124
references: Anticancer Res. 1996 May-Jun;16(3B):1485-9
references: 8694517
references: Science. 2000 Mar 17;287(5460):1969-73
references: 10720316
references: Int J Oncol. 1997 Sep;11(3):543-50
references: 21528245
references: Cancer Res. 2003 Jun 15;63(12):3195-201
references: 12810648
references: NMR Biomed. 2008 Aug;21(7):677-85
references: 18186027
references: Cancer Res. 1999 Jan 1;59(1):80-4
references: 9892190
references: Cancer Lett. 2004 Apr 8;206(2):137-48
references: 15013519
references: NMR Biomed. 2010 Jul;23(6):624-32
references: 20661875
references: Br J Cancer. 2001 Mar 2;84(5):691-6
references: 11237392
references: Oncogene. 2002 Jun 20;21(27):4317-22
references: 12082619
references: Mol Cancer Res. 2003 Sep;1(11):789-800
references: 14517341
references: J Lipid Res. 2012 Jan;53(1):149-57
references: 22025560
references: NMR Biomed. 2012 Apr;25(4):685-94
references: 21954105
references: Trends Mol Med. 2002;8(4 Suppl):S1-9
references: 11927279
references: FEBS Lett. 2006 Aug 21;580(19):4746-50
references: 16893542
references: IDrugs. 2001 Apr;4(4):419-26
references: 16015482
references: Methods Mol Biol. 2012;887:41-7
references: 22566045
references: Magn Reson Med. 1984 Dec;1(4):508-34
references: 6400586
references: J Neurooncol. 2007 Nov;85(2):133-48
references: 17874037
references: Oncogene. 2004 Oct 28;23(50):8247-59
references: 15378008
references: NMR Biomed. 1999 Nov;12(7):413-39
references: 10654290
references: Cancer Res. 2006 Jan 1;66(1):427-34
references: 16397258
references: Cell Death Dis. 2013;4:e933
references: 24287694
references: Int J Cancer. 1997 Nov 14;73(4):570-9
references: 9389574
references: Biochim Biophys Acta. 2005 May 1;1734(1):1-12
references: 15866478
references: Oncogene. 1997 Nov 6;15(19):2289-301
references: 9393874
references: Annu Rev Biochem. 1957;26:119-48
references: 13488391
references: NMR Biomed. 1994 May;7(3):149-55
references: 8080717
references: NMR Biomed. 2009 Apr;22(3):259-65
references: 19040203
references: Neuro Oncol. 2014 Sep;16(9):1167-75
references: 24642524
references: Nat Rev Cancer. 2011 Dec;11(12):835-48
references: 22089420
references: Mol Cancer Ther. 2014 Sep;13(9):2149-58
references: 25028471
references: Cancer Res. 2008 Jan 1;68(1):172-80
references: 18172309
references: Nat Med. 1999 Nov;5(11):1323-7
references: 10546002
references: Magn Reson Med. 1999 Apr;41(4):649-56
references: 10332839
references: Anal Quant Cytol Histol. 2001 Aug;23(4):291-9
references: 11531144
references: J Clin Neurosci. 2008 May;15(5):545-51
references: 18378459