Shen Yan, Cai Minxia, Xia Weiliang, Liu Junwei, Zhang Qiyi, Xie Haiyang, Wang Chen, Wang Xiaohui, Zheng Shusen
Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Department of Hepato-Biliary-Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China.
Cancer Lett. 2007 Sep 8;254(2):288-97. doi: 10.1016/j.canlet.2007.03.013. Epub 2007 Apr 25.
FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inducing apoptosis of lymphocytes [S. Suzuki, FTY720: Mechanisms of action and its effect on organ transplantation, Transplant. Proc. 31 (1999) 2779-2782]. Additionally, it has been found that FTY720 has inhibitory effects on various cancer growth and metastasis [J.D. Wang, S. Takahara, N. Nonomura, Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation, Prostate 40 (1999) 50-55]. To investigate its effect on the growth and metastasis of pancreatic cancer, FTY720 was used to treat three pancreatic cancer cell lines (BxPC-3, AsPC-1, and PANC-1). The MTT assay and flow cytometry were used to evaluate the cell death after FTY720 treatment; the wound closure assay, three-dimensional (3D) Matrigel assay, and invasive assay were used to evaluate the migration, colony formation and invasion abilities after FTY720 treatment, respectively. Protein expression in BxPC-3, AsPC-1, and PANC-1 cells after FTY720 treatment was detected by Western blotting. The MTT assay indicated that the growth of pancreatic cancer cells could be inhibited by FTY720 at various concentrations between 0 and 17 microM in a dose-dependent manner, which was also confirmed by flow cytometry. The wound closure assay, 3D Matrigel assay and cell invasion assay all showed that FTY720 significantly suppressed migration, colony formation and invasion ability of cancer cells at concentrations from 5 to 17 microM. After FTY720 treatment, the phospho-Akt, Bcl-2, pro-caspase-3 expression were down-regulated while the caspase-9 protein expression was increased. In conclusion, FTY720 can inhibit the growth, migration and invasion of pancreatic cancer cells. Our study provides a preclinical support for chemotherapeutic approach with FTY720 for the treatment of pancreatic cancer.
FTY720是一种通过对蝉拟青霉代谢产物进行修饰而产生的合成化合物，是一种独特的免疫抑制剂，通过诱导淋巴细胞凋亡发挥其活性[S. Suzuki，FTY720：作用机制及其对器官移植的影响，《移植过程》31（1999年）2779 - 2782]。此外，已发现FTY720对各种癌症的生长和转移具有抑制作用[J.D. Wang，S. Takahara，N. Nonomura，FTY720诱导雄激素非依赖性前列腺癌细胞系早期凋亡需要半胱天冬酶 - 3激活，《前列腺》40（1999年）50 - 55]。为了研究其对胰腺癌生长和转移的影响，使用FTY720处理三种胰腺癌细胞系（BxPC - 3、AsPC - 1和PANC - 1）。采用MTT法和流式细胞术评估FTY720处理后的细胞死亡情况；分别采用伤口愈合试验、三维（3D）基质胶试验和侵袭试验评估FTY720处理后的迁移、集落形成和侵袭能力。通过蛋白质印迹法检测FTY720处理后BxPC - 3、AsPC - 1和PANC - 1细胞中的蛋白质表达。MTT试验表明，FTY720在0至17微摩尔的不同浓度下均可剂量依赖性地抑制胰腺癌细胞的生长，流式细胞术也证实了这一点。伤口愈合试验、3D基质胶试验和细胞侵袭试验均表明，FTY720在5至17微摩尔的浓度下可显著抑制癌细胞的迁移、集落形成和侵袭能力。FTY720处理后，磷酸化Akt、Bcl - 2、前半胱天冬酶 - 3的表达下调，而半胱天冬酶 - 9蛋白表达增加。总之，FTY720可抑制胰腺癌细胞的生长、迁移和侵袭。我们的研究为FTY720用于治疗胰腺癌的化疗方法提供了临床前支持。
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