Background: We investigated whether cell cycle synchronization induced by the T-type calcium channel inhibitor mibefradil could increase tumoral 2-[18F] fluoro-2-deoxy-d-glucose (FDG) uptake in vitro and in vivo. Methods: Human prostate cancer cells (PC-3) were treated with 10 μM mibefradil for 24, 48, and 72 h to induce G1 arrest. Cell cycle distribution was analyzed at 0, 4, 8, 12, 15, 18, and 24 h after mibefradil withdrawal. Cellular uptake was measured after incubating cells with [3H] Deoxy-d-Glucose (DDG) for 1 h at the same time points used in the cell cycle analysis. The correlation between [3H] DDG uptake and each cell cycle phase was evaluated in the early (0–12 h) and late phases (15–24 h) of synchronization. In vivo FDG PET imaging was performed in PC-3-bearing mice at baseline, 24 h, and 48 h after mibefradil treatment. Results: The G0/G1 fraction of PC-3 cells was significantly increased from 33.1% ± 0.2% to 60.9% ± 0.8% after 24 h mibefradil treatment, whereas the S and G2/M fractions were decreased from 36.3% ± 1.4% to 23.2% ± 1.1% and from 29.7% ± 1.3% to 14.9% ± 0.9%, respectively, which were similar to the results by serum starvation. Mibefradil treatment for 24, 48, and 72 h increased the number of cells in S phase at 18–24 h after withdrawal; however, only the 72 h treatment increased [3H] DDG uptake (145.8 ± 5.8% of control at 24 h after withdrawal). [3H] DDG uptake was positively correlated with the size of the S phase fraction and negatively correlated with the size of the G0/G1 fraction in the late phase of synchronization. DDG uptake was significantly increased by mibefradil-induced cell cycle synchronization and correlated with the sizes of cell cycle fractions. In vivo FDG PET imaging also demonstrated a significant increase in tumor uptake after mibefradil treatment. Quantified tumor FDG uptake (%ID/g) increased from 4.13 ± 2.10 to 4.7 ± 2.16 at 24 h, and 5.95 ± 2.57 at 48 h (p< 0.05). Conclusion: Cell cycle synchronization could be used to increase the diagnostic sensitivity of clinical FDG positron emission tomography.
背景：本研究旨在探讨T型钙通道抑制剂米贝地尔诱导的细胞周期同步化能否在体外和体内增加肿瘤对2-[18F]氟-2-脱氧-D-葡萄糖（FDG）的摄取。方法：采用10 μM米贝地尔处理人前列腺癌细胞（PC-3）24、48和72小时以诱导G1期阻滞。在撤药后0、4、8、12、15、18和24小时分析细胞周期分布。在细胞周期分析的相同时间点，将细胞与[3H]脱氧-D-葡萄糖（DDG）孵育1小时后测定细胞摄取量。在同步化的早期（0-12小时）和晚期（15-24小时）阶段评估[3H]DDG摄取与各细胞周期时相的相关性。在荷PC-3肿瘤小鼠中，分别于米贝地尔治疗前、治疗后24小时和48小时进行FDG PET活体成像。结果：经24小时米贝地尔处理后，PC-3细胞的G0/G1期比例从33.1%±0.2%显著增加至60.9%±0.8%，而S期和G2/M期比例分别从36.3%±1.4%降至23.2%±1.1%、从29.7%±1.3%降至14.9%±0.9%，该结果与血清饥饿法诱导效果相似。24、48和72小时的米贝地尔处理均能在撤药后18-24小时增加S期细胞数量，但仅72小时处理能显著提升[3H]DDG摄取量（撤药24小时后达对照组的145.8±5.8%）。在同步化晚期阶段，[3H]DDG摄取与S期比例呈正相关，与G0/G1期比例呈负相关。米贝地尔诱导的细胞周期同步化显著增强DDG摄取，且该摄取量与细胞周期各时相比例具有相关性。活体FDG PET成像同样显示米贝地尔治疗后肿瘤摄取显著增加：定量肿瘤FDG摄取率（%ID/g）从基线4.13±2.10升至24小时的4.7±2.16，48小时进一步增至5.95±2.57（p<0.05）。结论：细胞周期同步化技术可用于提高临床FDG正电子发射断层扫描的诊断敏感性。
Modulation of FDG Uptake by Cell Cycle Synchronization Using a T-Type Calcium Channel Inhibitor
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