ArticleCancer research2009
Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia.
Article in Cancer research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 120 citations in OpenAlex.
- Pathway of LCK Tyrosine Kinase and mTOR Signaling in Children with T-Cell Acute Lymphoblastic Leukemia.The application of clinical genetics · 2024Review
- Ailanthone Inhibits Cell Proliferation in Tongue Squamous Cell Carcinoma via PI3K/AKT Pathway.Evidence-based complementary and alternative medicine : eCAM · 2022Article
- Redox Control in Acute Lymphoblastic Leukemia: From Physiology to Pathology and Therapeutic Opportunities.Cells · 2021Review
- T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies.Blood cancer discovery · 2021Review
- Dual Kinase Targeting in Leukemia.Cancers · 2021Review
- Development of a bioavailable boron-containing PI-103 Bioisostere, PI-103BE.Bioorganic & medicinal chemistry letters · 2020Article
- Autophagy in endothelial cells regulates their haematopoiesis-supporting ability.EBioMedicine · 2020Article
- Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of KCell communication and signaling : CCS · 2019Article
- Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update.International journal of molecular sciences · 2018Review
- Article
- Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells.Oncotarget · 2017Article
- Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2017Review
- Acute lymphoblastic leukemia: a comprehensive review and 2017 update.Blood cancer journal · 2017Review
- Signaling pathways as therapeutic targets in biliary tract cancer.Expert opinion on therapeutic targets · 2017Review
- Review
- Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells.International journal of hematology · 2015Article
- Outlook on PI3K/AKT/mTOR inhibition in acute leukemia.Molecular and cellular therapies · 2015Article
- Article
- Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice.Cancer biology & therapy · 2015Article
- Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia.Leukemia · 2014Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G(0)-G(1) phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3beta. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.