Dyshlovoy Sergey A, Hauschild Jessica, Kriegs Malte, Hoffer Konstantin, Burenina Olga Y, Strewinsky Nadja, Malyarenko Timofey V, Kicha Alla A, Ivanchina Natalia V, Stonik Valentin A, Graefen Markus, Bokemeyer Carsten, von Amsberg Gunhild
Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251, Hamburg, Germany.
Department of Radiotherapy and Radiation Oncology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251, Hamburg, Germany.
Sci Rep. 2025 Aug 4;15(1):28410. doi: 10.1038/s41598-025-12914-7.
Marine triterpene glycosides are known to exhibit significant anticancer activity. We investigated pacificusoside C and cucumariosides C and C isolated from a sea star Solaster pacificus in prostate cancer models with varying drug resistance and in non-cancerous cells in vitro. Cucumarioside C showed selectivity comparable to cisplatin, whereas the other compounds were less selective. Cucumarioside C induced apoptosis and enhanced cytotoxic effects of cisplatin, carboplatin, docetaxel, and cabazitaxel, making it a potential candidate for combination therapy. All three glycosides were active in docetaxel-resistant cells and were neither inhibitors nor substrates of P-glycoprotein, indicating P-glycoprotein-independent activity. To explore the mechanism of anticancer activity of cucumarioside C, we performed functional kinome profiling of treated 22Rv1 cells, predicting activation of kinases involved in stress response and survival (IKKα, IKKβ, IKKε), necroptosis (MLKL), metabolism (GCN2, PDK1), cytoskeletal dynamics (RHOK), mitophagy (PINK1), apoptosis and cell cycle regulation (PITSLRE), and immune modulation (COT). Notably, only MAP kinases p38 and ERK1/2 were predicted to be specifically inhibited, that was further validated by Western blotting. These findings may potentially explain previously reported anticancer effects of cucumarioside C and related marine glycosides. To our knowledge, this is the first study to report triterpene glycosides' effects on the kinome of cancer cells.
海洋三萜糖苷已知具有显著的抗癌活性。我们在具有不同耐药性的前列腺癌模型和体外非癌细胞中研究了从海星太平洋太阳海星中分离出的太平洋糖苷C以及海参糖苷C和C。海参糖苷C显示出与顺铂相当的选择性，而其他化合物的选择性较低。海参糖苷C诱导细胞凋亡并增强顺铂、卡铂、多西他赛和卡巴他赛的细胞毒性作用，使其成为联合治疗的潜在候选药物。所有这三种糖苷在多西他赛耐药细胞中均有活性，且既不是P-糖蛋白的抑制剂也不是其底物，表明其活性不依赖于P-糖蛋白。为了探究海参糖苷C的抗癌活性机制，我们对处理后的22Rv1细胞进行了功能激酶组分析，预测了参与应激反应和存活（IKKα、IKKβ、IKKε）、坏死性凋亡（MLKL）、代谢（GCN2、PDK1）、细胞骨架动力学（RHOK）、线粒体自噬（PINK1）、细胞凋亡和细胞周期调控（PITSLRE）以及免疫调节（COT）的激酶的激活。值得注意的是，只有丝裂原活化蛋白激酶p38和ERK1/2被预测会受到特异性抑制，这一点通过蛋白质印迹法得到了进一步验证。这些发现可能潜在地解释了先前报道的海参糖苷C和相关海洋糖苷的抗癌作用。据我们所知，这是第一项报道三萜糖苷对癌细胞激酶组影响的研究。
