Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China.
Biochem Pharmacol. 2024 May;223:116125. doi: 10.1016/j.bcp.2024.116125. Epub 2024 Mar 12.
Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/β-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, β-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/β-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.
膀胱癌（BC）是泌尿系统最常见的恶性肿瘤。虽然化疗是 BC 的重要辅助治疗方法之一，但耐药性、非特异性毒性和严重的副作用是 BC 化疗的主要障碍。天然产物一直是抗肿瘤药物发现的主要资源，具有疗效好、毒性低、多靶点、易得等优点。本研究评估了来源于垂序商陆 Securinega suffruticosa 的天然生物碱 securinine（SEC）在体外和体内对 BC 细胞的潜在抗肿瘤作用，并阐明了其潜在机制。结果发现，SEC 抑制 BC 细胞的增殖、迁移和侵袭，诱导 BC 细胞凋亡，抑制 BC 细胞的异种移植瘤生长。值得注意的是，SEC 具有良好的安全性，因为它对正常细胞和小鼠没有毒性或毒性较低。机制上，SEC 抑制 Wnt/β-catenin 信号通路，同时激活 p38 和 JNK 信号通路。此外，β-catenin 过表达、p38 抑制剂 SB203580 和 JNK 抑制剂 SP600125 均减轻了 SEC 对 BC 细胞的抑制作用。此外，我们还证明了 SEC 和吉西他滨（GEM）在体外和体内对 BC 细胞均具有协同抑制作用。综上所述，本研究结果提示 SEC 可能通过激活 p38 和 JNK 信号通路，抑制 Wnt/β-catenin 信号通路，发挥抗 BC 细胞作用。更有意义的是，研究结果表明，SEC 可增强 GEM 诱导的 BC 细胞杀伤作用。
