Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, 510080, People's Republic of China.
J Neurooncol. 2012 Aug;109(1):53-62. doi: 10.1007/s11060-012-0885-5. Epub 2012 May 5.
Malignant glioma is the most devastating and aggressive tumor in brain, characterized by rapid proliferation and diffuse invasion. Chemotherapy and radiotherapy are the pivotal strategies after surgery; however, high drug resistance of malignant glioma and the blood-brain barrier usually render chemotherapy drugs ineffective. Here, we find that triptolide, a small molecule with high lipid solubility, is capable of inhibiting proliferation and invasion of malignant glioma cells effectively. In both investigated malignant glioma cell lines, triptolide repressed cell proliferation via inducing cell cycle arrest in G0/G1 phase, associated with downregulation of G0/G1 cell cycle regulators cyclin D1, CDK4, and CDK6 followed by reduced phosphorylation of retinoblastoma protein (Rb). In addition, triptolide induced morphological change of C6 cells through downregulation of protein expression of MAP-2 and inhibition of activities of GTPases Cdc42 and Rac1/2/3, thus significantly suppressing migratory and invasive capacity. Moreover, in an in vivo tumor model, triptolide delayed growth of malignant glioma xenografts. These findings suggest an important inhibitory action of triptolide on proliferation and invasion of malignant glioma, and encourage triptolide as a candidate for glioma therapy.
恶性脑胶质瘤是最具破坏性和侵袭性的脑肿瘤，其特征为快速增殖和广泛浸润。化疗和放疗是手术后的关键策略；然而，恶性脑胶质瘤的高药物耐药性和血脑屏障通常使化疗药物无效。在这里，我们发现具有高脂溶性的小分子雷公藤红素能够有效抑制恶性脑胶质瘤细胞的增殖和侵袭。在两种研究的恶性脑胶质瘤细胞系中，雷公藤红素通过诱导细胞周期停滞在 G0/G1 期来抑制细胞增殖，伴随着 G0/G1 细胞周期调节剂 cyclin D1、CDK4 和 CDK6 的下调，随后视网膜母细胞瘤蛋白（Rb）的磷酸化减少。此外，雷公藤红素通过下调 MAP-2 的蛋白表达和抑制 GTPases Cdc42 和 Rac1/2/3 的活性，诱导 C6 细胞形态发生变化，从而显著抑制迁移和侵袭能力。此外，在体内肿瘤模型中，雷公藤红素延迟了恶性脑胶质瘤异种移植物的生长。这些发现表明雷公藤红素对恶性脑胶质瘤的增殖和侵袭具有重要的抑制作用，并鼓励将雷公藤红素作为脑肿瘤治疗的候选药物。
