PMID- 23580240
OWN - NLM
STAT- MEDLINE
DCOM- 20131107
LR  - 20211203
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 133
IP  - 8
DP  - 2013 Oct 15
TI  - Concurrent inhibition of PI3K and mTORC1/mTORC2 overcomes resistance to rapamycin 
      induced apoptosis by down-regulation of Mcl-1 in mantle cell lymphoma.
PG  - 1813-24
LID - 10.1002/ijc.28206 [doi]
AB  - Mantle cell lymphoma (MCL) is an aggressive form of Non-Hodgkin-lymphoma (NHL) 
      with an ongoing need for novel treatments. Apart from the translocation t(11:14), 
      which facilitates constitutive transcription of cyclin D1, additional aberrations 
      are frequently observed in MCL, including a recurrent dysregulation of the 
      phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of 
      rapamycin (mTOR) signaling pathway. mTOR, a key component of this pathway, is 
      pivotal for the assembly of mTOR complex (mTORC) 1 and 2. Temsirolimus, an analog 
      of the mTOR inhibitor rapamycin, is approved for the treatment of relapsed MCL. 
      Response rates, however, are low and response durations are short. We demonstrate 
      that inhibition of mTORC1 by rapamycin or blocking of mTORC1 and mTORC2 in 
      conjunction with PI3K by NVP-BEZ235 reduces proliferation of MCL cell lines to a 
      similar extent. However, only NVP-BEZ235 is able to sufficiently inhibit the 
      downstream pathway of mTOR and to mediate cell death through activation of the 
      intrinsic apoptosis pathway. Further analysis demonstrated that the 
      anti-apoptotic Bcl-2 family member Mcl-1 plays a central role in regulation of 
      MCL survival. While Mcl-1 protein levels remained unchanged after coculture with 
      rapamycin, they were down-regulated in NVP-BEZ235 treated cells. Furthermore, 
      inhibition of Mcl-1 by the BH3-only mimetic obatoclax or down-regulation of 
      constitutive Mcl-1, but not of Bcl-2 or Bcl-xL, by siRNA facilitated cell death 
      of MCL cells and enhanced NVP-BEZ235's capacity to induce cell death. Our 
      findings may help to lay the foundation for further improvements in the treatment 
      of MCL.
CI  - Copyright (c) 2013 UICC.
FAU - Muller, Anja
AU  - Muller A
AD  - Department of Hematology, Oncology and Tumor Immunology, University Medical 
      Center Charite, Campus Berlin-Buch, Humboldt University, Berlin, Germany.
FAU - Zang, Chuanbing
AU  - Zang C
FAU - Chumduri, Cindrilla
AU  - Chumduri C
FAU - Dorken, Bernd
AU  - Dorken B
FAU - Daniel, Peter T
AU  - Daniel PT
FAU - Scholz, Christian W
AU  - Scholz CW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130615
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Pyrroles)
RN  - 0 (Quinolines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (bcl-X Protein)
RN  - 0 (quinoline-val-asp(OMe)-CH2-OPH)
RN  - 136601-57-5 (Cyclin D1)
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 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Caspases)
RN  - QN4128B52A (obatoclax)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Apoptosis/drug effects
MH  - Caspase Inhibitors/pharmacology
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cyclin D1/genetics/metabolism
MH  - Down-Regulation
MH  - Drug Resistance, Neoplasm
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Indoles
MH  - Lymphoma, Mantle-Cell/*drug therapy/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Multiprotein Complexes/*antagonists & inhibitors
MH  - Myeloid Cell Leukemia Sequence 1 Protein
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins c-bcl-2/*biosynthesis/genetics
MH  - Pyrroles/pharmacology
MH  - Quinolines/pharmacology
MH  - RNA Interference
MH  - RNA, Small Interfering
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - bcl-X Protein/genetics
OTO - NOTNLM
OT  - AKT
OT  - Mcl-1
OT  - PI3K
OT  - mTOR
OT  - mantle cell lymphoma
OT  - signaling
EDAT- 2013/04/13 06:00
MHDA- 2013/11/08 06:00
CRDT- 2013/04/13 06:00
PHST- 2012/10/22 00:00 [received]
PHST- 2013/03/21 00:00 [accepted]
PHST- 2013/04/13 06:00 [entrez]
PHST- 2013/04/13 06:00 [pubmed]
PHST- 2013/11/08 06:00 [medline]
AID - 10.1002/ijc.28206 [doi]
PST - ppublish
SO  - Int J Cancer. 2013 Oct 15;133(8):1813-24. doi: 10.1002/ijc.28206. Epub 2013 Jun 
      15.