title: Rapamycin interacts synergistically with idarubicin to induce T-leukemia cell apoptosis in vitro and in a mesenchymal stem cell simulated drug-resistant microenvironment via Akt/mammalian target of rapamycin and extracellular signal-related kinase signaling pathways.
abstract: T-cell acute lymphoblastic leukemias (T-ALLs) are clonal lymphoid malignancies with a poor prognosis, and still a lack of effective treatment. Here we examined the interactions between the mammalian target of rapamycin (mTOR) inhibitor rapamycin and idarubicin (IDA) in a series of human T-ALL cell lines Molt-4, Jurkat, CCRF-CEM and CEM/C1. Co-exposure of cells to rapamycin and IDA synergistically induced T-ALL cell growth inhibition and apoptosis mediated by caspase activation via the intrinsic mitochondrial pathway and extrinsic pathway. Combined treatment with rapamycin and IDA down-regulated Bcl-2 and Mcl-1, and inhibited the activation of phosphoinositide 3-kinase (PI3K)/mTOR and extracellular signal-related kinase (ERK). They also played synergistic pro-apoptotic roles in the drug-resistant microenvironment simulated by mesenchymal stem cells (MSCs) as a feeder layer. In addition, MSCs protected T-ALL cells from IDA cytotoxicity by up-regulating ERK phosphorylation, while rapamycin efficiently reversed this protective effect. Taken together, we confirm the synergistic antitumor effects of rapamycin and IDA, and provide an insight into the potential future clinical applications of combined rapamycin-IDA regimens for treating T-cell malignancies.
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou , China.
authors.forename: Kang-Ni
authors.initials: KN
authors.lastname: Wu
authors.forename: Yan-Min
authors.initials: YM
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Bin-Sheng
authors.initials: BS
authors.lastname: Wang
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Du
authors.forename: Shan
authors.initials: S
authors.lastname: Fu
authors.forename: Kai-Min
authors.initials: KM
authors.lastname: Hu
authors.forename: Li-Fei
authors.initials: LF
authors.lastname: Zhang
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Liu
authors.forename: Yong-Xian
authors.initials: YX
authors.lastname: Hu
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Wang
authors.forename: He
authors.initials: H
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D015458:Leukemia, T-Cell / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus; D015255:Idarubicin