Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy
James A. McCubrey,Linda S. Steelman,Steve L. Abrams,Fred E. Bertrand,D. E. Ludwig,Jörg Bäsecke,Massimo Libra,Franca Stivala,M. Milella,Agostino Tafuri,Paolo Lunghi,Antonio Bonati,Alberto M. Martelli,Alberto M. Martelli +13 more
TLDR
It may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth.Abstract:
The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.read more
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The TRAIL apoptotic pathway in cancer onset, progression and therapy
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Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging
Linda S. Steelman,William H. Chappell,Stephen L. Abrams,C. Ruth Kempf,Jacquelyn M. Long,Piotr Laidler,Sanja Mijatović,Danijela Maksimović-Ivanić,Franca Stivala,Maria Clorinda Mazzarino,Marco Donia,Paolo Fagone,Graziella Malaponte,Ferdinando Nicoletti,Massimo Libra,Michele Milella,Agostino Tafuri,Antonio Bonati,Jörg Bäsecke,Lucio Cocco,Camilla Evangelisti,Alberto M. Martelli,Giuseppe Montalto,Melchiorre Cervello,James A. McCubrey +24 more
TL;DR: The functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli are discussed and the recently described roles of these pathways in cancer stem cells, cellular senescence and aging are evaluated.
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Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health
William H. Chappell,Linda S. Steelman,Jacquelyn M. Long,Ruth C. Kempf,Stephen L. Abrams,Richard A. Franklin,Jörg Bäsecke,Franca Stivala,Marco Donia,Paolo Fagone,Graziella Malaponte,Maria Clorinda Mazzarino,Ferdinando Nicoletti,Massimo Libra,Danijela Maksimović-Ivanić,Sanja Mijatović,Giuseppe Montalto,Melchiorre Cervello,Piotr Laidler,Michele Milella,Agostino Tafuri,Antonio Bonati,Camilla Evangelisti,Lucio Cocco,Alberto M. Martelli,James A. McCubrey +25 more
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Redox regulation in cancer: a double-edged sword with therapeutic potential.
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Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor
Matthew R. Janes,Jose J. Limon,Lomon So,Jing Chen,Raymond J Lim,Melissa A Chavez,Collin Vu,Michael B. Lilly,Sharmila Mallya,S. Tiong Ong,Marina Konopleva,Michael B. Martin,Pingda Ren,Yi Liu,Christian Rommel,David A. Fruman +15 more
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