Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: Possible clinical application of mTOR inhibitor

Hirase, Chikara; Maeda, Yasuhiro; Takaı̈, Shinji; Kanamaru, Akihisa

doi:10.1016/j.leukres.2008.07.023

Cited by 41 publications

(39 citation statements)

References 45 publications

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“…[132] Since that initial report, the activity of a number of rapalogs, including everolimus, sirolimus, and temsirolimus have been extensively studied in ALL in preclinical models by our group and others, establishing activity not only in cell lines and transgenic mouse models, but also against primary human ALL samples supported in vitro with stromal cells and in vivo with immunodeficient mouse strains. [131,132,[134][135][136][137][138][139][140] Our work and the work of others suggest that rapalogs may have the highest degree of activity against ALL types with the worst prognosis, including pre-T, adult, BCR-ABL and Ikaros mutant. [29,135,141,142] Supporting this are recent data demonstrating that early engraftment of pre-B-ALL in immune-deficient mice is associated with the activation of the mTOR pathway and a very high risk of relapse.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 52%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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Section: Acute Lymphoblastic Leukemiamentioning

confidence: 52%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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“…1C). SU/SR is an imatinib-resistant subline of SU-Ph2 established after long-term culture of SU-Ph2 in the presence of increasing concentrations of imatinib (23) and has the T315I mutation of BCR-ABL in one of two BCR-ABL genes (Supplementary Fig. S3A; ref.…”

Section: Downregulation Of Cdk4 By Inactivation Of Bcr-abl In Phmentioning

confidence: 99%

“…SU-Ph2 and TCCY are imatinib-sensitive cell lines established from patients with Ph þ ALL, and SU/SR and TCCY/SR are their imatinib-resistant sublines, respectively, obtained after long-term culture with increasing concentrations of imatinib (23,24). SK-9 was established from a Ph þ ALL patient who relapsed after chemotherapy combined with imatinib (25).…”

Section: Introductionmentioning

confidence: 99%

“…SU/SR, TCCY/SR, and SK-9 were confirmed to have the T315I mutation of BCR-ABL. KOPN, KOCL, YAMN, YACL, and KOPT series of cell lines were sequentially established in our laboratory from 1980 to 2011 as previously reported (21,22), SU-Ph2 and SU/SR were established by Y. Maeda (23) and provided in 2010, TCCY and TCCY/SR were established by Y. Sato (24) and provided in 2011, SK9 was established by S. Okabe (25) and provided in 2012, and Reh, Jurkat, and MOLT4 were purchased from ATCC in 2000. Nalm1, Nalm6, 697, UOCB1, and HALO1 were kindly provided by Dr. Thomas Look (Dana-Farber Cancer Institute, Boston, MA) in 1997.…”

Section: Introductionmentioning

confidence: 99%

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Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

Nemoto

Saida

Kato

et al. 2016

Molecular Cancer Therapeutics

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S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph þ ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph þ ALL. In particular, PD0332991exhibited extremely high antileukemic activity against CML-LC and Ph þ ALL cell lines in the nanomolar range by the induction of G 0 -G 1 arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition.

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“…Studies have indicated that the molecules of mTOR pathway were concerned with tumorigenesis and mTOR inhibitors (rapamycin and RAD001) could affect sensitivity of tumors (including leukemias) to various forms of therapy (9)(10)(11)(12)(13). The result of the recent studies also indicated that the signaling pathway of mTOR became an important therapeutic target for leukemias (14,15). However, understanding of the role of mTOR pathway in tumorigenesis and the impact of rapamycin in clinic treatment of myelogenous leukemia is unclear, and more studies need to be done.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin provides a therapeutic option through inhibition of mTOR signaling in chronic myelogenous leukemia

Luo¹

2011

Oncol Rep

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Abstract. Chronic myelogenous leukemia (CML) is a neoplasm of myeloid progenitor cells expressing Bcr-Abl fusion protein.However, some patients with CML are less likely to respond to imatinib, the inhibitor of Bcr-Abl kinase. Recent studies showed that mTOR pathway can increase responses to imatinib. The analysis of mTOR pathway in CML may provide new insights into possible targets of novel therapies. Therefore, we examined the expression of mTOR pathway molecules in bone marrow cells from CML patients and effect of rapamycin on K562 cells in vitro. Western blot analysis showed the visibly higher phosphorylation of mTOR (70.6%), 4E-BP1 (76.5%) and p70S6K (73.5%) in bone marrow cells from CML patients. Moreover, treatment of CML cell line (K562) with rapamycin resulted in a decrease of phosphorylation of mTOR, 4E-BP1 and p70S6K. In vitro, the cell viability in groups with rapamycin treatment displayed a significant decrease in a dose-dependent manner by MTT. The data presented an increase of G 0 /G 1 phase cells and decrease of S phase cells after rapamycin treatment, and the decreased expression of cyclinD1, higher expression of p21 at mRNA level was also detected in K562 with rapamycin. Treatment with 20 nmol/l or more rapamycin could increase apoptotic cells, decrease expression of bcl-2 and activate caspase-3. In conclusion, the mTOR pathway might be involved in chronic myelogenous leukemia. Inhibition of mTOR pathway could interfer with cell proliferation and increase cell apoptosis in K562 cells. It suggested that mTOR might be an important therapeutic target for myelogenous leukemia.

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Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: Possible clinical application of mTOR inhibitor

Cited by 41 publications

References 45 publications

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

Rapamycin provides a therapeutic option through inhibition of mTOR signaling in chronic myelogenous leukemia

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