PMID- 25535978
OWN - NLM
STAT- MEDLINE
DCOM- 20151103
LR  - 20211203
IS  - 1473-5741 (Electronic)
IS  - 0959-4973 (Linking)
VI  - 26
IP  - 4
DP  - 2015 Apr
TI  - The antileukemia roles of PP242 alone or in combination with daunorubicin in 
      acute leukemia.
PG  - 410-21
LID - 10.1097/CAD.0000000000000200 [doi]
AB  - PP242 is a novel dual mammalian target of rapamycin (mTOR) inhibitor that 
      simultaneously inhibits mTORC1 and mTORC2, and its antileukemia effect has been 
      sufficiently investigated here. The human acute leukemia cell lines and primary 
      blasts were treated with PP242 alone or in combination with daunorubicin (DNR). 
      Cell proliferation was examined using an MTT assay. The phosphorylation 
      expression of the Akt/mTORC1/eIF4E signaling pathway was assessed by western blot 
      analysis. The assembly of the eIF4F translation initiation complex was examined 
      using a 7-methyl-guanosine cap affinity assay. PP242 significantly induced 
      cytotoxicity in human acute leukemia cells, especially in combination with DNR. 
      The phosphorylation levels of eIF4E (p-eIF4E) at Ser209 influence the 
      antileukemia roles of PP242. As expected, the antiproliferative effects of PP242 
      on leukemia cells with low p-eIF4E expression, such as the acute promyelocytic 
      leukemia NB4 cell line and AML-M3 primary blasts, were poor. Surprisingly, the 
      effects of PP242 in leukemia cells with high p-eIF4E expression, such as the 
      acute myelomonocytic leukemia THP-1 cell line and M4-M5 primary blasts, were also 
      weak. In contrast, PP242 exerted a significant antiproliferative effect in the 
      Ph+ acute lymphoblastic leukemia SUP-B15 cell line and the mantle cell lymphoma 
      JEKO-1 cell line, which had intermediate p-eIF4E levels. PP242 inhibited the 
      translation of the antiapoptotic protein Mcl-1 by downregulating the 
      Akt/mTORC1/eIF4E signaling pathway. More importantly, DNR activated the 
      Akt/mTORC1/eIF4E signaling pathway, whereas PP242 effectively eliminated this 
      deleterious side effect of DNR and synergistically enhanced the anticancer 
      ability of DNR treatment. PP242, especially in combination with DNR, exerts 
      significant antileukemia effects.
FAU - Shi, Fangfang
AU  - Shi F
AD  - Department of Hematology, West China Hospital, Sichuan University, Chengdu, 
      China.
FAU - Yang, Xiaojing
AU  - Yang X
FAU - Gong, Yuping
AU  - Gong Y
FAU - Shi, Rui
AU  - Shi R
FAU - Yang, Xi
AU  - Yang X
FAU - Naren, Duolan
AU  - Naren D
FAU - Wu, Jiahui
AU  - Wu J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Anticancer Drugs
JT  - Anti-cancer drugs
JID - 9100823
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Indoles)
RN  - 0 (MCL1 protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Purines)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H5669VNZ7V (PP242)
RN  - ZS7284E0ZP (Daunorubicin)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Daunorubicin/*pharmacology
MH  - Drug Synergism
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Humans
MH  - Indoles/*pharmacology
MH  - Leukemia/*pathology
MH  - Leukemia, Myelomonocytic, Acute/pathology
MH  - Leukemia, Promyelocytic, Acute/pathology
MH  - Lymphoma, Mantle-Cell/pathology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes/metabolism
MH  - Myeloid Cell Leukemia Sequence 1 Protein/metabolism
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Purines/*pharmacology
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2014/12/24 06:00
MHDA- 2015/11/04 06:00
CRDT- 2014/12/24 06:00
PHST- 2014/12/24 06:00 [entrez]
PHST- 2014/12/24 06:00 [pubmed]
PHST- 2015/11/04 06:00 [medline]
AID - 10.1097/CAD.0000000000000200 [doi]
PST - ppublish
SO  - Anticancer Drugs. 2015 Apr;26(4):410-21. doi: 10.1097/CAD.0000000000000200.