The Phosphoinositide 3-Kinase Inhibitor PI-103 Downregulates Choline Kinase α Leading to Phosphocholine and Total Choline Decrease Detected by Magnetic Resonance Spectroscopy
| Autor: | Juan Carlos Lacal, L. Elizabeth Jackson, Nada M.S. Al-Saffar, Ana Ramírez de Molina, Martin O. Leach, Florence I. Raynaud, Paul A. Clarke, Paul Workman |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Cancer Research Magnetic Resonance Spectroscopy Choline kinase Pyridines Phosphorylcholine Phosphoinositide 3-kinase inhibitor Down-Regulation Adenocarcinoma Article Choline Phosphatidylinositol 3-Kinases chemistry.chemical_compound Cell Line Tumor Choline Kinase Humans PTEN Furans PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Phosphocholine biology PTEN Phosphohydrolase Membrane Proteins Prostatic Neoplasms HCT116 Cells Molecular biology Fatty acid synthase Pyrimidines Oncology chemistry biology.protein |
| Zdroj: | Cancer Research. 70:5507-5517 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-09-4476 |
| Popis: | The phosphoinositide 3-kinase (PI3K) pathway is a major target for cancer drug development. PI-103 is an isoform-selective class I PI3K and mammalian target of rapamycin inhibitor. The aims of this work were as follows: first, to use magnetic resonance spectroscopy (MRS) to identify and develop a robust pharmacodynamic (PD) biomarker for target inhibition and potentially tumor response following PI3K inhibition; second, to evaluate mechanisms underlying the MRS-detected changes. Treatment of human PTEN null PC3 prostate and PIK3CA mutant HCT116 colon carcinoma cells with PI-103 resulted in a concentration- and time-dependent decrease in phosphocholine (PC) and total choline (tCho) levels (P < 0.05) detected by phosphorus (31P)- and proton (1H)-MRS. In contrast, the cytotoxic microtubule inhibitor docetaxel increased glycerophosphocholine and tCho levels in PC3 cells. PI-103–induced MRS changes were associated with alterations in the protein expression levels of regulatory enzymes involved in lipid metabolism, including choline kinase α (ChoKα), fatty acid synthase (FAS), and phosphorylated ATP-citrate lyase (pACL). However, a strong correlation (r2 = 0.9, P = 0.009) was found only between PC concentrations and ChoKα expression but not with FAS or pACL. This study identified inhibition of ChoKα as a major cause of the observed change in PC levels following PI-103 treatment. We also showed the capacity of 1H-MRS, a clinically well-established technique with higher sensitivity and wider applicability compared with 31P-MRS, to assess response to PI-103. Our results show that monitoring the effects of PI3K inhibitors by MRS may provide a noninvasive PD biomarker for PI3K inhibition and potentially of tumor response during early-stage clinical trials with PI3K inhibitors. Cancer Res; 70(13); 5507–17. ©2010 AACR. |
| Databáze: | OpenAIRE |
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