title: The antileukemia roles of PP242 alone or in combination with daunorubicin in acute leukemia.
abstract: 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.
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Shi
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
authors.forename: Yuping
authors.initials: Y
authors.lastname: Gong
authors.forename: Rui
authors.initials: R
authors.lastname: Shi
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Duolan
authors.initials: D
authors.lastname: Naren
authors.forename: Jiahui
authors.initials: J
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007938:Leukemia / Q000473:pathology*; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D007211:Indoles; C579095:MCL1 protein, human; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011687:Purines; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D003630:Daunorubicin