PMID- 26506264
OWN - NLM
STAT- MEDLINE
DCOM- 20160913
LR  - 20231213
IS  - 1551-4005 (Electronic)
IS  - 1538-4101 (Print)
IS  - 1551-4005 (Linking)
VI  - 14
IP  - 22
DP  - 2015
TI  - p21(WAF1) modulates drug-induced apoptosis and cell cycle arrest in B-cell 
      precursor acute lymphoblastic leukemia.
PG  - 3602-12
LID - 10.1080/15384101.2015.1100774 [doi]
AB  - p21(WAF1) is a well-characterized mediator of cell cycle arrest and may also 
      modulate chemotherapy-induced cell death. The role of p21(WAF1) in drug-induced 
      cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was 
      investigated using p53-functional patient-derived xenografts (PDXs), in which 
      p21(WAF1) was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell 
      precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX 
      cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine 
      (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite 
      dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, 
      both ALL subtypes exhibited similar cell death kinetics and were equally 
      sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly 
      more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA 
      suppression of p21(WAF1) in the BCP-ALL 697 cell line resulted in a moderate 
      depletion of the cell fraction in G1 phase and marked increase in PS 
      externalization following exposure to etoposide. Furthermore, stable lentiviral 
      p21(WAF1) silencing in the BCP-ALL Nalm-6 cell line accelerated PS 
      externalization and cell death following exposure to etoposide and vorinostat, 
      supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited 
      p21(WAF1) expression in Nalm-6 cells exposed to vorinostat and also partially 
      augmented vorinostat-induced cell death. Taken together, these findings 
      demonstrate that p21(WAF1) regulates the early stages of drug-induced apoptosis 
      in ALL cells and significantly modulates their sensitivity to vorinostat.
FAU - Davies, Carwyn
AU  - Davies C
AD  - a Children's Cancer Institute ; Lowy Cancer Research Centre; UNSW Australia ; 
      Sydney , NSW , Australia.
AD  - c Clinical Pharmacology Modeling and Simulation ; GlaxoSmithKline R&D ; Sydney , 
      Australia.
FAU - Hogarth, Linda A
AU  - Hogarth LA
AD  - b Northern Institute for Cancer Research ; Newcastle University; Newcastle upon 
      Tyne ; Tyne and Wear , UK.
FAU - Mackenzie, Karen L
AU  - Mackenzie KL
AD  - a Children's Cancer Institute ; Lowy Cancer Research Centre; UNSW Australia ; 
      Sydney , NSW , Australia.
FAU - Hall, Andrew G
AU  - Hall AG
AD  - b Northern Institute for Cancer Research ; Newcastle University; Newcastle upon 
      Tyne ; Tyne and Wear , UK.
FAU - Lock, Richard B
AU  - Lock RB
AD  - a Children's Cancer Institute ; Lowy Cancer Research Centre; UNSW Australia ; 
      Sydney , NSW , Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Phosphatidylserines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Sp1 Transcription Factor)
RN  - 0 (SP1 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 53YET703F2 (terameprocol)
RN  - 58IFB293JI (Vorinostat)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 7BO8G1BYQU (Masoprocol)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (CASP7 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 7)
SB  - IM
MH  - Antineoplastic Agents, Phytogenic/pharmacology
MH  - Apoptosis/drug effects
MH  - B-Lymphocytes/*drug effects/metabolism/pathology
MH  - Caspase 3/genetics/metabolism
MH  - Caspase 7/genetics/metabolism
MH  - Cell Cycle Checkpoints/*drug effects
MH  - Cell Line, Tumor
MH  - Cyclin-Dependent Kinase Inhibitor p21/antagonists & 
      inhibitors/*genetics/metabolism
MH  - Etoposide/pharmacology
MH  - *Gene Expression Regulation, Leukemic
MH  - Histone Deacetylase Inhibitors/*pharmacology
MH  - Humans
MH  - Hydroxamic Acids/*pharmacology
MH  - Masoprocol/analogs & derivatives/pharmacology
MH  - Phosphatidylserines/metabolism
MH  - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug 
      therapy/genetics/metabolism/pathology
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug 
      therapy/genetics/metabolism/pathology
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Signal Transduction
MH  - Sp1 Transcription Factor/antagonists & inhibitors/genetics/metabolism
MH  - T-Lymphocytes/drug effects/metabolism/pathology
MH  - Transcription, Genetic
MH  - Tumor Suppressor Protein p53/genetics/metabolism
MH  - Vorinostat
PMC - PMC4825786
OTO - NOTNLM
OT  - childhood acute lymphoblastic leukemia
OT  - etoposide
OT  - p21WAF1
OT  - patient derived xenograft models
OT  - terameprocol
OT  - vorinostat
EDAT- 2015/10/28 06:00
MHDA- 2016/09/14 06:00
PMCR- 2016/10/27
CRDT- 2015/10/28 06:00
PHST- 2015/10/28 06:00 [entrez]
PHST- 2015/10/28 06:00 [pubmed]
PHST- 2016/09/14 06:00 [medline]
PHST- 2016/10/27 00:00 [pmc-release]
AID - 1100774 [pii]
AID - 10.1080/15384101.2015.1100774 [doi]
PST - ppublish
SO  - Cell Cycle. 2015;14(22):3602-12. doi: 10.1080/15384101.2015.1100774.