Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
Cancer Sci. 2012 Jun;103(6):1099-104. doi: 10.1111/j.1349-7006.2012.02246.x. Epub 2012 Mar 15.
Pancreatic cancer is highly metastatic and has a poor prognosis. However, there is no established treatment for pancreatic cancer. Lysophosphatidic acid (LPA) has been shown to be present in effluents of cancers and involved in migration and proliferation in a variety of cancer cells, including pancreatic cancer cells, in vitro. In the current study, we examined whether an orally active LPA antagonist is effective for pancreatic cancer tumorigenesis and metastasis in vivo. Oral administration of Ki16198, which is effective for LPA(1) and LPA(3), into YAPC-PD pancreatic cancer cell-inoculated nude mice significantly inhibited tumor weight and remarkably attenuated invasion and metastasis to lung, liver, and brain, in association with inhibition of matrix metalloproteinase (MMP) accumulation in ascites in vivo. Ki16198 inhibited LPA-induced migration and invasion in several pancreatic cancer cells in vitro, which was associated with the inhibition of LPA-induced MMP production. In conclusion, Ki16198 is a promising orally active LPA antagonist for inhibiting the invasion and metastasis of pancreatic cancer cells. The inhibitory effects of the antagonist on invasion and metastasis in vivo may be partially explained by the inhibition of motility activity and MMP production in cancer cells.
胰腺癌具有高度转移性和预后不良的特点。然而，目前还没有针对胰腺癌的既定治疗方法。溶血磷脂酸（LPA）已被证明存在于癌症流出物中，并在体外的各种癌细胞中参与迁移和增殖，包括胰腺癌细胞。在本研究中，我们研究了口服活性 LPA 拮抗剂在体内对胰腺癌肿瘤发生和转移的影响。口服 LPA(1)和 LPA(3)有效药物 Ki16198 显著抑制 YAPC-PD 胰腺癌细胞接种裸鼠的肿瘤重量，并显著减弱对肺、肝和脑的侵袭和转移，同时抑制腹水基质金属蛋白酶（MMP）的积累。Ki16198 抑制了几种胰腺癌细胞中 LPA 诱导的迁移和侵袭，这与抑制 LPA 诱导的 MMP 产生有关。综上所述，Ki16198 是一种有前途的口服活性 LPA 拮抗剂，可抑制胰腺癌细胞的侵袭和转移。该拮抗剂对体内侵袭和转移的抑制作用可能部分解释为抑制癌细胞的迁移活性和 MMP 产生。
