Li Xiaoli, Wang Guoli, Zhou Xiaolin, Zhao Huijie, Chen Xiaojie, Cui Qixiao, Li Minjing, Gao Xihang, Wei Xiaoyu, Ye Lei, Li Defang, Hong Pan
Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
Phytother Res. 2023 Oct;37(10):4740-4754. doi: 10.1002/ptr.7943. Epub 2023 Aug 9.
Gastric cancer (GC) is one of the most common malignant tumors worldwide. Thus, the development of safe and effective therapeutic compounds for GC treatment is urgently required. Here, we aimed to examine the role of picropodophyllin (PPP), a compound extracted from the rhizome of Dysosma versipellis (Hance) M. Cheng ex Ying, on the proliferation of GC cells. Our study revealed that PPP inhibits the proliferation of GC cells in a dose-dependent manner by inducing apoptosis. Moreover, our study elucidated that PPP suppresses the growth of GC tumor xenografts with no side effects of observable toxicity. Mechanistically, PPP exerts its effects by blocking the AKT/mammalian target of rapamycin (mTOR) signaling pathway; these effects are markedly abrogated by the overexpression of constitutively active AKT. Furthermore, drug affinity responsive target stability (DARTS) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) revealed that heat shock protein 90 (HSP90) may be a potential target of PPP. Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.
胃癌（GC）是全球最常见的恶性肿瘤之一。因此，迫切需要开发用于GC治疗的安全有效的治疗性化合物。在此，我们旨在研究从八角莲（Dysosma versipellis (Hance) M. Cheng ex Ying）根茎中提取的化合物小檗碱（PPP）对GC细胞增殖的作用。我们的研究表明，PPP通过诱导凋亡以剂量依赖性方式抑制GC细胞的增殖。此外，我们的研究阐明，PPP可抑制GC肿瘤异种移植瘤的生长，且无明显的毒性副作用。机制上，PPP通过阻断AKT/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路发挥作用；组成型活性AKT的过表达可显著消除这些作用。此外，药物亲和力响应靶点稳定性（DARTS）和液相色谱-串联质谱（LC-MS/MS）显示，热休克蛋白90（HSP90）可能是PPP的潜在靶点。表面等离子体共振和免疫沉淀试验证实，PPP直接靶向HSP90并破坏HSP90与AKT的结合，从而抑制GC细胞增殖。因此，我们的研究表明，PPP可能是一种有前途的GC治疗性化合物。
