PMID- 27385099
OWN - NLM
STAT- MEDLINE
DCOM- 20180223
LR  - 20181113
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 31
DP  - 2016 Aug 2
TI  - The anti-cancer activity of the mTORC1/2 dual inhibitor XL388 in preclinical 
      osteosarcoma models.
PG  - 49527-49538
LID - 10.18632/oncotarget.10389 [doi]
AB  - 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.
FAU - Zhu, Yun-Rong
AU  - Zhu YR
AD  - Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of 
      Southeast University, Jiangyin City, 215600, China.
FAU - Zhou, Xiao-Zhong
AU  - Zhou XZ
AD  - The Department of Orthopedics, The Second Affiliated Hospital of Soochow 
      University, Suzhou 215000, China.
FAU - Zhu, Lun-Qing
AU  - Zhu LQ
AD  - The Center of Diagnosis and Treatment for Children's Bone Diseases, The 
      Children's Hospital Affiliated to Soochow University, Suzhou, Jiangsu, 215000, 
      China.
FAU - Yao, Chen
AU  - Yao C
AD  - Joint group of Orthopedic Department, Affiliated Hospital of Nanjing University 
      of TCM, Nanjing 210029, China.
FAU - Fang, Jian-Feng
AU  - Fang JF
AD  - Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of 
      Southeast University, Jiangyin City, 215600, China.
FAU - Zhou, Feng
AU  - Zhou F
AD  - Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of 
      Southeast University, Jiangyin City, 215600, China.
FAU - Deng, Xiong-Wei
AU  - Deng XW
AD  - Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of 
      Southeast University, Jiangyin City, 215600, China.
FAU - Zhang, Yun-Qing
AU  - Zhang YQ
AD  - Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of 
      Southeast University, Jiangyin City, 215600, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Beclin-1)
RN  - 0 (Sulfones)
RN  - 0 (XL388)
RN  - 5142-23-4 (3-methyladenine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 3.4.22.- (Caspases)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/analogs & derivatives/pharmacology
MH  - Adolescent
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Autophagy
MH  - Beclin-1/metabolism
MH  - Bone Neoplasms/*drug therapy
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Gene Silencing
MH  - Humans
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/*metabolism
MH  - Mice
MH  - Mice, SCID
MH  - Neoplasm Transplantation
MH  - Osteosarcoma/*drug therapy/metabolism
MH  - Phosphorylation
MH  - Sulfones/*pharmacology
MH  - Treatment Outcome
MH  - Tumor Cells, Cultured
MH  - Young Adult
PMC - PMC5226526
OTO - NOTNLM
OT  - AKT
OT  - XL388
OT  - autophagy and chemo-sensitization
OT  - mTORC1/2
OT  - osteosarcoma (OS)
COIS- All listed authors state no conflicts of interest.
EDAT- 2016/07/08 06:00
MHDA- 2018/02/24 06:00
PMCR- 2016/08/02
CRDT- 2016/07/08 06:00
PHST- 2016/04/24 00:00 [received]
PHST- 2016/06/09 00:00 [accepted]
PHST- 2016/07/08 06:00 [pubmed]
PHST- 2018/02/24 06:00 [medline]
PHST- 2016/07/08 06:00 [entrez]
PHST- 2016/08/02 00:00 [pmc-release]
AID - 10389 [pii]
AID - 10.18632/oncotarget.10389 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Aug 2;7(31):49527-49538. doi: 10.18632/oncotarget.10389.