The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo
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Fei Shi1,*, Jinying Zhang2,*, Hongyu Liu3, Liangliang Wu3, Hongyu Jiang4, Qiyan Wu3, Tianyi Liu3, Meiqing Lou1,# and Hao Wu5,#
1Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China
2Institute of Basic Medicine Science, Chinese PLA General Hospital, Beijing 100853, China
3Key Laboratory of Cancer Center, Chinese PLA General Hospital, Beijing 100853, China
4Department of Anesthesiology, Wuxi Third People’s Hospital, Wuxi, Jiangsu 214000, China
5Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
*These authors contributed equally to this work
Hao Wu, email: [email protected]
Meiqing Lou, email: [email protected]
Keywords: chemotherapy; dactolisib (NVP-BEZ235); dual PI3K/mTOR inhibitor; glioblastoma; radiotherapy
Received: October 15, 2017 Accepted: December 01, 2017 Published: December 09, 2017
Glioblastomas (GBMs) are among the most malignant of all human tumors and have poor prognosis. The current standard of care (SOC) includes maximal surgical tumor resection followed by adjuvant temozolomide (TMZ) and concomitant radiotherapy (RT). However, even with this treatment, the 5-year survival rate is less than 10%, and thus, follow-up treatment is required to improve efficacy. In GBMs as well as many other solid cancers, PI3K/mTOR signaling is overactivated. Therefore, multiple tumor-based PI3K inhibitors have been studied in various cancers. In the current study, we investigated the effect of the dual PI3K/mTOR inhibitor dactolisib on TMZ+RT treatment in three human GBM cell lines and a orthotopic xenograft model. Dactolisib alone induced cytotoxicity and pro-apoptotic effects, which act as antitumor factors. Combined with SOC treatment, dactolisib inhibited cell viability, induced enhanced pro-apoptotic effect, and attenuated migration/invasion in all three cell lines, thereby enhancing the SOC therapeutic effect. Protein microarray analysis showed that A172 cells treated with TMZ+RT+dactolisib had higher p27 and lower Bcl-2 expression than other groups. Moreover, in the xenograft model, oral dactolisib combined with TMZ+RT inhibited tumor growth and prolonged survival. Thus, SOC combined with dactolisib shows potent anti-tumor activity and has promising potential for solid tumor treatment.
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