University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA.
Breast Cancer Res Treat. 2012 Apr;132(3):1001-8. doi: 10.1007/s10549-011-1675-z. Epub 2011 Jul 15.
Frondoside A, derived from the sea cucumber Cucumaria frondosa has demonstrable anticancer activity in several models, however, the ability of Frondoside A to affect tumor metastasis has not been reported. Using a syngeneic murine model of metastatic breast cancer, we now show that Frondoside A has potent antimetastatic activity. Frondoside A given i.p. to mice bearing mammary gland-implanted mammary tumors, inhibits spontaneous tumor metastasis to the lungs. The elevated Cyclooxygenase-2 activity in many malignancies promotes tumor growth and metastasis by producing high levels of PGE(2) which acts on the prostaglandin E receptors, chiefly EP4 and EP2. We examined the ability of Frondoside A to modulate the functions of these EP receptors. We now show that Frondoside A antagonizes the prostaglandin E receptors EP2 and EP4. (3)H-PGE(2) binding to recombinant EP2 or EP4-expressing cells was inhibited by Frondoside A at low μM concentrations. Likewise, EP4 or EP2-linked activation of intracellular cAMP as well as EP4-mediated ERK1/2 activation were also inhibited by Frondoside A. Consistent with the antimetastatic activity observed in vivo, migration of tumor cells in vitro in response to EP4 or EP2 agonists was also inhibited by Frondoside A. These studies identify a new function for an agent with known antitumor activity, and show that the antimetastatic activity may be due in part to a novel mechanism of action. These studies add to the growing body of evidence that Frondoside A may be a promising new agent with potential to treat cancer and may also represent a potential new modality to antagonize EP4.
海参皂苷 A 来源于海参 Cucumaria frondosa，在几种模型中均表现出明显的抗癌活性，但海参皂苷 A 影响肿瘤转移的能力尚未见报道。我们使用同源性小鼠乳腺癌转移模型，现在表明海参皂苷 A 具有很强的抗转移活性。腹腔内给予患有乳腺植入性乳腺癌的小鼠海参皂苷 A，可抑制肿瘤自发转移至肺部。许多恶性肿瘤中升高的环氧化酶-2 活性通过产生高水平的 PGE（2）来促进肿瘤生长和转移，PGE（2）作用于前列腺素 E 受体，主要是 EP4 和 EP2。我们研究了海参皂苷 A 调节这些 EP 受体功能的能力。现在我们表明，海参皂苷 A 拮抗前列腺素 E 受体 EP2 和 EP4。（3）H-PGE（2）与重组 EP2 或 EP4 表达细胞的结合在低 μM 浓度下被海参皂苷 A 抑制。同样，EP4 或 EP2 连接的细胞内 cAMP 激活以及 EP4 介导的 ERK1/2 激活也被海参皂苷 A 抑制。与体内观察到的抗转移活性一致，肿瘤细胞在体外对 EP4 或 EP2 激动剂的迁移也被海参皂苷 A 抑制。这些研究确定了一种具有已知抗肿瘤活性的药物的新功能，并表明抗转移活性部分可能归因于一种新的作用机制。这些研究增加了越来越多的证据表明，海参皂苷 A 可能是一种有前途的新药物，具有治疗癌症的潜力，并且也可能代表拮抗 EP4 的一种新的潜在方式。
