PMID- 21083937
OWN - NLM
STAT- MEDLINE
DCOM- 20110318
LR  - 20211020
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 29
IP  - 1
DP  - 2010 Nov 18
TI  - Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis.
PG  - 150
LID - 10.1186/1756-9966-29-150 [doi]
AB  - BACKGROUND: Glucocorticoid (GC) resistance is frequently seen in acute 
      lymphoblastic leukemia of T-cell lineage (T-ALL). In this study we investigate 
      the potential and mechanism of using rapamycin to restore the sensitivity of 
      GC-resistant T-ALL cells to dexamethasone (Dex) treatment. METHODS: Cell 
      proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)- 
      2,5-diphenyltetrazolium bromide (MTT) assay. Fluorescence-activated cell sorting 
      (FACS) analysis was used to analyze apoptosis and cell cycles. Western blot 
      analysis was performed to test the expression of the downstream effector proteins 
      of mammalian target of rapamycin (mTOR), the cell cycle regulatory proteins, and 
      apoptosis associated proteins. RESULTS: 10 nM rapamycin markedly increased GC 
      sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in 
      part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated 
      with modulation of G1-S phase regulators. Both rapamycin and Dex can induce 
      up-regulation of cyclin-dependent kinase (CDK) inhibitors of p21 and p27 and 
      co-treatment of rapamycin with Dex resulted in a synergistic induction of their 
      expressions. Rapamycin did not obviously affect the expression of cyclin A, 
      whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced 
      expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 
      expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not 
      achieved by modulation of glucocorticoid receptor (GR) expression, but 
      synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and 
      Bim, and down-regulation of anti-apoptotic protein of Mcl-1. CONCLUSION: Our data 
      suggests that rapamycin can effectively reverse GC resistance in T-ALL and this 
      effect is achieved by inducing cell cycles arrested at G0/G1 phase and activating 
      the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor 
      rapamycin with GC containing protocol might be an attracting new therapeutic 
      approach for GC resistant T-ALL patients.
FAU - Gu, Ling
AU  - Gu L
AD  - Department of Pediatrics, West China Second University Hospital, Sichuan 
      University, Chengdu, China.
FAU - Zhou, Chenyan
AU  - Zhou C
FAU - Liu, Huajun
AU  - Liu H
FAU - Gao, Ju
AU  - Gao J
FAU - Li, Qiang
AU  - Li Q
FAU - Mu, Dezhi
AU  - Mu D
FAU - Ma, Zhigui
AU  - Ma Z
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101118
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (Antineoplastic Agents)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Blotting, Western
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Separation
MH  - Dexamethasone/*pharmacology
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Drug Synergism
MH  - Flow Cytometry
MH  - Humans
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy
MH  - Sirolimus/*pharmacology
PMC - PMC2998469
EDAT- 2010/11/19 06:00
MHDA- 2011/03/19 06:00
PMCR- 2010/11/18
CRDT- 2010/11/19 06:00
PHST- 2010/09/27 00:00 [received]
PHST- 2010/11/18 00:00 [accepted]
PHST- 2010/11/19 06:00 [entrez]
PHST- 2010/11/19 06:00 [pubmed]
PHST- 2011/03/19 06:00 [medline]
PHST- 2010/11/18 00:00 [pmc-release]
AID - 1756-9966-29-150 [pii]
AID - 10.1186/1756-9966-29-150 [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2010 Nov 18;29(1):150. doi: 10.1186/1756-9966-29-150.