Nagahashi Masayuki, Komatsu Miki, Urano Sayaka, Kuroiwa Mamiko, Takahashi Yuria, Morimoto Koji, Pradipta Ambara R, Tanaka Katsunori, Miyoshi Yasuo
Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo Medical University, Nishinomiya, Japan.
Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Institute of Science Tokyo, Ookayama, Japan.
Cancer Res Commun. 2025 Jun 1;5(6):981-993. doi: 10.1158/2767-9764.CRC-25-0023.
We developed a novel FTY720 prodrug (pro-FTY) that specifically inhibits sphingosine-1-phosphate signaling in cancer cells using a novel drug delivery system that reacts with acrolein. Our objective was to evaluate the efficacy and safety of pro-FTY in preclinical experiments. Ten breast cancer cell lines, two multidrug-resistant cell lines, and one normal mammary cell line were used to compare the IC50 values of pro-FTY with those of other drugs. Patient-derived organoids (PDO) were established and utilized for IC50 value comparisons. Drug efficacy was tested in mice bearing either syngeneic 4T1 cell tumors or patient-derived xenograft tumors, and blood analysis (including mass spectrometry) was performed. FTY720 and pro-FTY inhibited the survival of all breast cancer cell lines, including multidrug-resistant cells resistant to paclitaxel or doxorubicin. Unlike pro-FTY, FTY720 inhibited the survival of normal breast cell lines, suggesting that pro-FTY does not affect normal breast cells. Pro-FTY showed reproducible activity against multidrug-resistant PDOs, whereas paclitaxel and doxorubicin did not. Mass spectrometric analysis of pro-FTY-treated mice showed that FTY720 accumulated in tumors but was barely detectable in blood. Importantly, lymphocytopenia occurred in FTY720-treated mice but not in pro-FTY-treated mice. Furthermore, intravenous pro-FTY treatment significantly suppressed tumor growth in mice bearing patient-derived xenograft tumors generated from multidrug-resistant PDOs. In conclusion, pro-FTY inhibited breast cancer, including multidrug-resistant breast cancer, while avoiding lymphocytopenia, highlighting its clinical potential.
Pro-FTY selectively inhibits sphingosine-1-phosphate signaling in cancer cells using a novel acrolein-responsive drug delivery system that reacts with acrolein. Pro-FTY does not inhibit normal cell growth, thus avoiding lymphocytopenia. Pro-FTY is effective against multidrug-resistant breast cancer with a unique mechanism of action, highlighting its translational and therapeutic potential.
我们开发了一种新型的FTY720前药（pro-FTY），它使用一种与丙烯醛反应的新型药物递送系统，特异性抑制癌细胞中的鞘氨醇-1-磷酸信号传导。我们的目的是在临床前实验中评估pro-FTY的疗效和安全性。使用10种乳腺癌细胞系、2种多药耐药细胞系和1种正常乳腺细胞系来比较pro-FTY与其他药物的半数抑制浓度（IC50）值。建立了患者来源的类器官（PDO）并用于IC50值比较。在携带同基因4T1细胞肿瘤或患者来源的异种移植肿瘤的小鼠中测试药物疗效，并进行血液分析（包括质谱分析）。FTY720和pro-FTY抑制所有乳腺癌细胞系的存活，包括对紫杉醇或阿霉素耐药的多药耐药细胞。与pro-FTY不同，FTY720抑制正常乳腺细胞系的存活，这表明pro-FTY不影响正常乳腺细胞。Pro-FTY对多药耐药的PDO显示出可重复的活性，而紫杉醇和阿霉素则没有。对pro-FTY处理的小鼠进行质谱分析表明，FTY720在肿瘤中积累，但在血液中几乎检测不到。重要的是，FTY720处理的小鼠出现淋巴细胞减少，而pro-FTY处理的小鼠没有。此外，静脉注射pro-FTY治疗显著抑制了携带由多药耐药PDO产生的患者来源异种移植肿瘤的小鼠的肿瘤生长。总之，pro-FTY抑制乳腺癌，包括多药耐药乳腺癌，同时避免淋巴细胞减少，突出了其临床潜力。
Pro-FTY使用一种与丙烯醛反应的新型丙烯醛响应药物递送系统，选择性抑制癌细胞中的鞘氨醇-1-磷酸信号传导。Pro-FTY不抑制正常细胞生长，从而避免淋巴细胞减少。Pro-FTY通过独特的作用机制对多药耐药乳腺癌有效，突出了其转化和治疗潜力。
