Prestwich Glenn D, Gajewiak Joanna, Zhang Honglu, Xu Xiaoyu, Yang Guanghui, Serban Monica
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108, USA.
Biochim Biophys Acta. 2008 Sep;1781(9):588-94. doi: 10.1016/j.bbalip.2008.03.008. Epub 2008 Apr 8.
Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and also biochemical resistance to chemotherapy- and radiotherapy-induced apoptosis. LPA and its analogues also are feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, a.k.a., autotaxin, ATX), a central regulator of invasion and metastasis. For cancer therapy, the optimal therapeutic profile would be a metabolically-stabilized, pan-LPA receptor antagonist that also inhibited lysoPLD. For protection of gastrointestinal mucosa and lymphocytes, LPA agonists would be desirable to minimize or reverse radiation or chemical-induced injury. Analogues of lysophosphatidic acid (LPA) that are chemically modified to be less susceptible to phospholipases and phosphatases show activity as long-lived receptor-specific agonists and antagonists for LPA receptors, as well as inhibitors for the lysoPLD activity of ATX.
溶血磷脂酸（LPA）G蛋白偶联受体（GPCR）的亚型选择性激动剂和拮抗剂在细胞生物学和治疗中具有重要的潜在应用。LPA GPCR调节癌细胞的增殖、侵袭、血管生成，以及对化疗和放疗诱导的细胞凋亡的生化抗性。LPA及其类似物也是溶血磷脂酶D（lysoPLD，又名自分泌运动因子，ATX）的反馈抑制剂，lysoPLD是侵袭和转移的核心调节因子。对于癌症治疗，最佳治疗方案是一种代谢稳定的泛LPA受体拮抗剂，它还能抑制lysoPLD。为了保护胃肠道黏膜和淋巴细胞，LPA激动剂将有助于将辐射或化学诱导的损伤降至最低或逆转。经化学修饰使其不易被磷脂酶和磷酸酶作用的溶血磷脂酸（LPA）类似物，表现出作为LPA受体的长效受体特异性激动剂和拮抗剂的活性，以及作为ATX的lysoPLD活性抑制剂的活性。
