PMID- 23866964
OWN - NLM
STAT- MEDLINE
DCOM- 20140505
LR  - 20211203
IS  - 1756-8722 (Electronic)
IS  - 1756-8722 (Linking)
VI  - 6
DP  - 2013 Jul 18
TI  - Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce 
      autophagic cell death in Burkitt leukemia/lymphoma.
PG  - 53
LID - 10.1186/1756-8722-6-53 [doi]
AB  - BACKGROUND: Burkitt leukemia/lymphoma is a major subtype of aggressive B-cell 
      lymphoma. Biological targeted therapies on this disease need to be further 
      investigated and may help to improve the clinical outcome of the patients. 
      METHODS: This study examined the anti-tumor activity of the histone deacetylases 
      (HDAC) inhibitor valproic acid (VPA) combined with the mammalian target of 
      rapamycin (MTOR) inhibitor temsirolimus in Burkitt leukemia/lymphoma cell lines, 
      as well as in primary tumor cells and a murine xenograft model. RESULTS: 
      Co-treatment of VPA and temsirolimus synergistically inhibited the tumor cell 
      growth and triggered the autophagic cell death, with a significant inhibition of 
      MTOR signaling and MYC oncoprotein. Functioned as a class I HDAC inhibitor, VPA 
      potentiated the effect of temsirolimus on autophagy through inhibiting HDAC1. 
      Molecular silencing of HDAC1 using small interfering RNA (siRNA) attenuated 
      VPA-mediated regulation of CDKN1A, CDKN1B and LC3-I/II, regression of tumor cell 
      growth and induction of autophagy. Meanwhile, VPA counteracted 
      temsirolimus-induced AKT activation via HDAC3 inhibition. HDAC3 siRNA abrogated 
      the ability of VPA to modulate AKT phosphorylation, to suppress tumor cell growth 
      and to induce autophagy. Strong antitumor effect was also observed on primary 
      tumor cells while sparing normal hematopoiesis ex vivo. In a murine xenograft 
      model established with subcutaneous injection of Namalwa cells, dual treatment 
      efficiently blocked tumor growth, inhibited MYC and induced in situ autophagy. 
      CONCLUSIONS: These findings confirmed the synergistic effect of the HDAC and MTOR 
      inhibitors on Burkitt leukemia/lymphoma, and provided an insight into clinical 
      application of targeting autophagy in treating MYC-associated lymphoid 
      malignancies.
FAU - Dong, Li Hua
AU  - Dong LH
AD  - State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, 
      Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 
      Shanghai, China.
FAU - Cheng, Shu
AU  - Cheng S
FAU - Zheng, Zhong
AU  - Zheng Z
FAU - Wang, Li
AU  - Wang L
FAU - Shen, Yang
AU  - Shen Y
FAU - Shen, Zhi Xiang
AU  - Shen ZX
FAU - Chen, Sai Juan
AU  - Chen SJ
FAU - Zhao, Wei Li
AU  - Zhao WL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130718
PL  - England
TA  - J Hematol Oncol
JT  - Journal of hematology & oncology
JID - 101468937
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Autophagy/drug effects
MH  - Burkitt Lymphoma/*drug therapy/enzymology/pathology
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - Histone Deacetylase Inhibitors/*pharmacology
MH  - Humans
MH  - Mice
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Valproic Acid/*pharmacology
MH  - Xenograft Model Antitumor Assays
PMC - PMC3722002
EDAT- 2013/07/23 06:00
MHDA- 2014/05/06 06:00
PMCR- 2013/07/18
CRDT- 2013/07/23 06:00
PHST- 2013/05/13 00:00 [received]
PHST- 2013/07/14 00:00 [accepted]
PHST- 2013/07/23 06:00 [entrez]
PHST- 2013/07/23 06:00 [pubmed]
PHST- 2014/05/06 06:00 [medline]
PHST- 2013/07/18 00:00 [pmc-release]
AID - 1756-8722-6-53 [pii]
AID - 10.1186/1756-8722-6-53 [doi]
PST - epublish
SO  - J Hematol Oncol. 2013 Jul 18;6:53. doi: 10.1186/1756-8722-6-53.