Orally active lysophosphatidic acid receptor antagonist attenuates pancreatic cancer invasion and metastasis in vivo
Orally active lysophosphatidic acid receptor antagonist attenuates pancreatic cancer invasion and metastasis in vivo
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DOI：
10.1111/j.1349-7006.2012.02246.x
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发表时间：
2012-06-01
期刊：
影响因子：
5.7
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Komachi, Mayumi;Sato, Koichi;Okajima, Fumikazu
胰腺癌转移率高，预后差。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)存在于癌症的分泌物中，并在体外参与包括胰腺癌细胞在内的多种癌细胞的迁移和增殖。在目前的研究中，我们研究了口服活性LPA拮抗剂是否对体内胰腺癌的发生和转移有效。对LPA1和LPA3有效的Ki16198对接种YAPC-PD胰腺癌细胞的裸鼠有显著的抑瘤作用，并能显著减轻肿瘤对肺、肝、脑的侵袭和转移，同时抑制腹水中基质金属蛋白酶的积聚。Ki16198在体外可抑制LPA诱导的几种胰腺癌细胞的迁移和侵袭，这与抑制LPA诱导的基质金属蛋白酶的产生有关。结论：Ki16198是一种有前景的口服活性LPA拮抗剂，可抑制胰腺癌细胞的侵袭和转移。拮抗剂对体内侵袭转移的抑制作用可能部分是通过抑制癌细胞的运动活性和基质金属蛋白酶的产生来实现的。(《癌症科学》2012年版，第103期：10991104页)
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 LPA1 and LPA3, 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. (Cancer Sci 2012; 103: 10991104)