Synergism between the phosphatidylinositol 3-kinase p110β isoform inhibitor AZD6482 and the mixed lineage kinase 3 inhibitor URMC-099 on the blockade of glioblastoma cell motility and focal adhesion formation

Cancer Cell International

Jing Liu¹  Wen-lan Liu¹  Wei-ping Li¹  Peng-yu Diao¹  Xian-jian Huang¹  Yan-wen Xu¹  Guo-dong Huang¹  Hua-fu Zhao¹  Chang-peng Wu²  Xiu-ming Zhou³  Jing Wang⁴  Zhong-ping Chen⁴ 

[1] Department of Neurosurgery, Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, 518035, Shenzhen, China;Department of Neurosurgery, Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, 518035, Shenzhen, China;Department of Neurosurgery, People’s Hospital of Longhua District, 518109, Shenzhen, China;Department of Neurosurgery, Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, 518035, Shenzhen, China;Epilepsy Center, Guangdong 999 Brain Hospital, 510510, Guangzhou, China;Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China;

关键词: Glioblastoma;    PI3K;    p110β;    MLK3;    Synergism;   

DOI  :  10.1186/s12935-020-01728-4

来源: Springer

【 摘 要 】

BackgroundGlioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Our previous studies delineated a crosstalk between PI3K/Akt and JNK signaling pathways, and a moderate anti-glioblastoma synergism caused by the combined inhibition of PI3K p110β (PI3Kβ) isoform and JNK. However, this combination strategy is not potent enough. MLK3, an upstream regulator of ERK and JNK, may replace JNK to exert stronger synergism with PI3Kβ.MethodsTo develop a new combination strategy with stronger synergism, the expression pattern and roles of MLK3 in glioblastoma patient’s specimens and cell lines were firstly investigated. Then glioblastoma cells and xenografts in nude mice were treated with the PI3Kβ inhibitor AZD6482 and the MLK3 inhibitor URMC-099 alone or in combination to evaluate their combination effects on tumor cell growth and motility. The combination effects on cytoskeletal structures such as lamellipodia and focal adhesions were also evaluated.ResultsMLK3 protein was overexpressed in both newly diagnosed and relapsing glioblastoma patients’ specimens. Silencing of MLK3 using siRNA duplexes significantly suppressed migration and invasion, but promoted attachment of glioblastoma cells. Combined inhibition of PI3Kβ and MLK3 exhibited synergistic inhibitory effects on glioblastoma cell proliferation, migration and invasion, as well as the formation of lamellipodia and focal adhesions. Furthermore, combination of AZD6482 and URMC-099 effectively decreased glioblastoma xenograft growth in nude mice. Glioblastoma cells treated with this drug combination showed reduced phosphorylation of Akt and ERK, and decreased protein expression of ROCK2 and Zyxin.ConclusionTaken together, combination of AZD6482 and URMC-099 showed strong synergistic anti-tumor effects on glioblastoma in vitro and in vivo. Our findings suggest that combined inhibition of PI3Kβ and MLK3 may serve as an attractive therapeutic approach for glioblastoma multiforme.

【 授权许可】

CC BY