Beloueche-Babari Mounia, Jackson L Elizabeth, Al-Saffar Nada M S, Eccles Suzanne A, Raynaud Florence I, Workman Paul, Leach Martin O, Ronen Sabrina M
Cancer Research UK Clinical Magnetic Resonance Research Group, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
Mol Cancer Ther. 2006 Jan;5(1):187-96. doi: 10.1158/1535-7163.MCT-03-0220.
Phosphoinositide 3-kinase (PI3K) is an attractive target for novel mechanism-based anticancer treatment. We used magnetic resonance (MR) spectroscopy (MRS) to detect biomarkers of PI3K signaling inhibition in human breast cancer cells. MDA-MB-231, MCF-7, and Hs578T cells were treated with the prototype PI3K inhibitor LY294002, and the (31)P MR spectra of cell extracts were monitored. In every case, LY294002 treatment was associated with a significant decrease in phosphocholine levels by up to 2-fold (P < 0.05). In addition, a significant increase in glycerophosphocholine levels by up to 5-fold was also observed (P <or= 0.05), whereas the content of glycerophosphoethanolamine, when detectable, did not change significantly. Nucleotide triphosphate levels did not change significantly in MCF-7 and MDA-MB-231 cells but decreased by approximately 1.3-fold in Hs578T cells (P = 0.01). The changes in phosphocholine and glycerophosphocholine levels seen in cell extracts were also detectable in the (31)P MR spectra of intact MDA-MB-231 cells following exposure to LY294002. When treated with another PI3K inhibitor, wortmannin, MDA-MB-231 cells also showed a significant decrease in phosphocholine content by approximately 1.25-fold relative to the control (P < 0.05), whereas the levels of the remaining metabolites did not change significantly. Our results indicate that PI3K inhibition in human breast cancer cells by LY294002 and wortmannin is associated with a decrease in phosphocholine levels.
磷酸肌醇3激酶（PI3K）是基于新作用机制的抗癌治疗的一个有吸引力的靶点。我们使用磁共振（MR）波谱（MRS）来检测人乳腺癌细胞中PI3K信号抑制的生物标志物。用原型PI3K抑制剂LY294002处理MDA-MB-231、MCF-7和Hs578T细胞，并监测细胞提取物的³¹P MR波谱。在每种情况下，LY294002处理均与磷酸胆碱水平显著降低高达2倍相关（P < 0.05）。此外，还观察到甘油磷酸胆碱水平显著升高高达5倍（P≤0.05），而甘油磷酸乙醇胺的含量在可检测时没有显著变化。在MCF-7和MDA-MB-231细胞中，三磷酸核苷酸水平没有显著变化，但在Hs578T细胞中降低了约1.3倍（P = 0.01）。在暴露于LY294002后的完整MDA-MB-231细胞的³¹P MR波谱中也可检测到细胞提取物中磷酸胆碱和甘油磷酸胆碱水平的变化。当用另一种PI3K抑制剂渥曼青霉素处理时，MDA-MB-231细胞的磷酸胆碱含量相对于对照也显著降低了约1.25倍（P < 0.05），而其余代谢物的水平没有显著变化。我们的结果表明，LY294002和渥曼青霉素对人乳腺癌细胞中PI3K的抑制与磷酸胆碱水平的降低有关。
