Oncotarget

Research Papers:

The anti-cancer activity of the mTORC1/2 dual inhibitor XL388 in preclinical osteosarcoma models

Yun-Rong Zhu, Xiao-zhong Zhou, Lun-qing Zhu, Chen Yao, Jian-Feng Fang, Feng Zhou, Xiong-Wei Deng and Yun-Qing Zhang _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:49527-49538. https://doi.org/10.18632/oncotarget.10389

Metrics: PDF 1280 views  |   HTML 1922 views  |   ?  


Abstract

Yun-Rong Zhu1,*, Xiao-zhong Zhou2,*, Lun-qing Zhu3,*, Chen Yao4, Jian-Feng Fang1, Feng Zhou1, Xiong-Wei Deng1, Yun-Qing Zhang1

1Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, 215600, China

2The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000, China

3The Center of Diagnosis and Treatment for Children’s Bone Diseases, The Children’s Hospital Affiliated to Soochow University, Suzhou, Jiangsu, 215000, China

4Joint group of Orthopedic Department, Affiliated Hospital of Nanjing University of TCM, Nanjing 210029, China

*Co-first authors

Correspondence to:

Yun-Qing Zhang, email: dryunqingzhang@163.com

Keywords: osteosarcoma (OS), mTORC1/2, XL388, AKT, autophagy and chemo-sensitization

Received: April 24, 2016     Accepted: June 09, 2016     Published: July 02, 2016

ABSTRACT

In the present study, we investigated the activity of XL388, a novel mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, in preclinical osteosarcoma (OS) models. XL388 was cytotoxic, cytostatic and pro-apoptotic to multiple established OS cell lines and primary human OS cells. XL388 blocked mTORC1/2 activation and downregulated cyclin D1/B1 expressions in OS cells, leaving AKT Thr-308 phosphorylation un-affected. Intriguingly, AKT1 T308A mutation potentiated XL388-induced cytotoxicity in OS cells. XL388 activated cytoprotective autophagy in OS cells. Autophagy inhibition, either pharmacologically or genetically, augmented XL388-induced anti-OS activity. Further, XL388 oral administration inhibited U2OS xenografts growth in severe combined immuno-deficient (SCID) mice. Such activity was enhanced with co-administration of the autophagy inhibitor 3-methyladenine (3-MA). Similarly, Beclin-1-silenced U2OS xenografts were remarkably more sensitive to XL388. Thus, concurrent blockage of mTORC1/2 with XL388 may have therapeutic value for OS.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 10389