Schmidt Claudia, Loos Cornelia, Jin Lu, Schmiech Michael, Schmidt Christoph Q, Gaafary Menna El, Syrovets Tatiana, Simmet Thomas
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany.
Present address: Rommelag CMO, Sulzbach-Laufen, Germany.
Oncotarget. 2017 Jul 8;8(33):55147-55161. doi: 10.18632/oncotarget.19101. eCollection 2017 Aug 15.
The triterpenoid acetyl-lupeolic acid (ac-LA) isolated from the oleogum resin of reduced the viability of a panel of cancer cell lines more efficiently than lupeol. There was no detectable intracellular conversion of ac-LA to lupeol and . In contrast to docetaxel, ac-LA did not induce selection of treatment-resistant cancer cells. By various parameters including DNA fragmentation, ac-LA was shown to induce apoptosis in androgen-independent PC-3 cells, whereas in MDA-MB-231 breast cancer cells, ac-LA led to cell accumulation in the G/M phase of the cell cycle, but not to apoptosis. docking combined with kinase assays implied that ac LA potently inhibits Akt mainly by direct binding to the pleckstrin homology domain. Consistently, an Akt1 mutant deficient of the PH domain afforded partial resistance to ac-LA and complete resistance to lupeol and the Akt inhibitor III. Ac-LA inhibited phosphorylation of downstream targets of the Akt signaling pathway, which was followed by inhibition of the mTOR target p70 ribosomal six protein kinase and the nuclear accumulation of p65/NF-κB, β-catenin, and c-myc, as well as loss of the mitochondrial membrane potential. Ac-LA exhibited antiproliferative, proapoptotic, and antitumorigenic effects on PC-3-tumors xenografted either on chick chorioallantoic membranes or in nude mice. Ac-LA exhibited a clearly better safety profile than docetaxel or lupeol during chronic administration . In contrast to lupeol, ac-LA also inhibited release of vascular endothelial growth factor and accordingly angiogenesis . Thus, ac-LA deserves further exploration as a potential new antitumor compound.
从[植物名称]油胶树脂中分离出的三萜类化合物乙酰羽扇豆醇酸（ac-LA）比羽扇豆醇更有效地降低了一组癌细胞系的活力。未检测到ac-LA在细胞内转化为羽扇豆醇。与多西他赛不同，ac-LA不会诱导产生耐药性癌细胞。通过包括DNA片段化在内的各种参数表明，ac-LA可诱导雄激素非依赖性PC-3细胞凋亡，而在MDA-MB-231乳腺癌细胞中，ac-LA导致细胞周期停滞在G/M期，但不会诱导凋亡。分子对接结合激酶分析表明，ac-LA主要通过直接结合到普列克底物蛋白同源结构域来有效抑制Akt。一致地，缺乏PH结构域的Akt1突变体对ac-LA产生部分抗性，对羽扇豆醇和Akt抑制剂III产生完全抗性。ac-LA抑制Akt信号通路下游靶点的磷酸化，随后抑制mTOR靶点p70核糖体S6蛋白激酶以及p65/NF-κB、β-连环蛋白和c-myc的核积累，同时线粒体膜电位丧失。ac-LA对在鸡胚绒毛尿囊膜或裸鼠体内异种移植的PC-3肿瘤具有抗增殖、促凋亡和抗肿瘤作用。在长期给药期间，ac-LA的安全性明显优于多西他赛或羽扇豆醇。与羽扇豆醇不同，ac-LA还抑制血管内皮生长因子的释放，从而抑制血管生成。因此，ac-LA作为一种潜在的新型抗肿瘤化合物值得进一步研究。
