PMID- 28662162
OWN - NLM
STAT- MEDLINE
DCOM- 20170928
LR  - 20211204
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 6
DP  - 2017
TI  - BKM120 induces apoptosis and inhibits tumor growth in medulloblastoma.
PG  - e0179948
LID - 10.1371/journal.pone.0179948 [doi]
LID - e0179948
AB  - Medulloblastoma (MB) is the most common malignant brain tumor in children, 
      accounting for nearly 20 percent of all childhood brain tumors. New treatment 
      strategies are needed to improve patient survival outcomes and to reduce adverse 
      effects of current therapy. The phosphatidylinositol-3-kinase 
      (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway 
      plays a key role in cellular metabolism, proliferation, survival and 
      angiogenesis, and is often constitutively activated in human cancers, providing 
      unique opportunities for anticancer therapeutic intervention. The aim of this 
      study was to evaluate the pre-clinical activity of BKM120, a selective pan-class 
      I PI3K inhibitor, on MB cell lines and primary samples. IC50 values of BKM120 in 
      the twelve MB cell lines tested ranged from 0.279 to 4.38 muM as determined by 
      cell viability assay. IncuCyte ZOOM Live-Cell Imaging system was used for kinetic 
      monitoring of cytotoxicity of BKM120 and apoptosis in MB cells. BKM120 exhibited 
      cytotoxicity in MB cells in a dose and time-dependent manner by inhibiting 
      activation of downstream signaling molecules AKT and mTOR, and activating 
      caspase-mediated apoptotic pathways. Furthermore, BKM120 decreased cellular 
      glycolytic metabolic activity in MB cell lines in a dose-dependent manner 
      demonstrated by ATP level per cell. In MB xenograft mouse study, DAOY cells were 
      implanted in the flank of nude mice and treated with vehicle, BKM120 at 30 mg/kg 
      and 60 mg/kg via oral gavage daily. BKM120 significantly suppressed tumor growth 
      and prolonged mouse survival. These findings help to establish a basis for 
      clinical trials of BKM120, which could be a novel therapy for the treatment of 
      medulloblastoma patients.
FAU - Zhao, Ping
AU  - Zhao P
AD  - Pediatric Oncology Translational Research Program, Helen DeVos Children's 
      Hospital, Grand Rapids, MI, United States of America.
FAU - Hall, Jacob
AU  - Hall J
AD  - Calvin College, Grand Rapids, MI, United States of America.
FAU - Durston, Mary
AU  - Durston M
AD  - Pediatric Oncology Translational Research Program, Helen DeVos Children's 
      Hospital, Grand Rapids, MI, United States of America.
FAU - Voydanoff, Austin
AU  - Voydanoff A
AD  - College of Human Medicine, Michigan State University, Grand Rapids, MI, United 
      States of America.
FAU - VanSickle, Elizabeth
AU  - VanSickle E
AD  - Pediatric Oncology Translational Research Program, Helen DeVos Children's 
      Hospital, Grand Rapids, MI, United States of America.
FAU - Kelly, Shannon
AU  - Kelly S
AD  - Pediatric Oncology Translational Research Program, Helen DeVos Children's 
      Hospital, Grand Rapids, MI, United States of America.
FAU - Nagulapally, Abhinav B
AU  - Nagulapally AB
AD  - Pediatric Oncology Translational Research Program, Helen DeVos Children's 
      Hospital, Grand Rapids, MI, United States of America.
FAU - Bond, Jeffery
AU  - Bond J
AD  - Pediatric Oncology Translational Research Program, Helen DeVos Children's 
      Hospital, Grand Rapids, MI, United States of America.
FAU - Saulnier Sholler, Giselle
AU  - Saulnier Sholler G
AUID- ORCID: 0000-0003-4561-2679
AD  - Pediatric Oncology Translational Research Program, Helen DeVos Children's 
      Hospital, Grand Rapids, MI, United States of America.
AD  - College of Human Medicine, Michigan State University, Grand Rapids, MI, United 
      States of America.
LA  - eng
PT  - Journal Article
DEP - 20170629
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Aminopyridines)
RN  - 0 (Morpholines)
RN  - 0 (NVP-BKM120)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (RNA, Neoplasm)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Aminopyridines/*pharmacology
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Medulloblastoma/*pathology
MH  - Mice
MH  - Morpholines/*pharmacology
MH  - Phosphatidylinositol 3-Kinase/genetics/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - RNA, Neoplasm/genetics
MH  - Survival Analysis
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC5491106
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2017/07/01 06:00
MHDA- 2017/09/29 06:00
PMCR- 2017/06/29
CRDT- 2017/06/30 06:00
PHST- 2017/01/24 00:00 [received]
PHST- 2017/06/07 00:00 [accepted]
PHST- 2017/06/30 06:00 [entrez]
PHST- 2017/07/01 06:00 [pubmed]
PHST- 2017/09/29 06:00 [medline]
PHST- 2017/06/29 00:00 [pmc-release]
AID - PONE-D-17-03218 [pii]
AID - 10.1371/journal.pone.0179948 [doi]
PST - epublish
SO  - PLoS One. 2017 Jun 29;12(6):e0179948. doi: 10.1371/journal.pone.0179948. 
      eCollection 2017.