2018
DOI: 10.1016/j.jbior.2018.03.001
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Dual inhibition of PI3K/mTOR signaling in chemoresistant AML primary cells

Abstract: A main cause of treatment failure for AML patients is resistance to chemotherapy. Survival of AML cells may depend on mechanisms that elude conventional drugs action and/or on the presence of leukemia initiating cells at diagnosis, and their persistence after therapy. MDR1 gene is an ATP-dependent drug efflux pump known to be a risk factor for the emergence of resistance, when combined to unstable cytogenetic profile of AML patients. In the present study, we analyzed the sensitivity to conventional chemotherap… Show more

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Cited by 17 publications
(20 citation statements)
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“…About 50-80% of patients with AML display constitutive PI3K/Akt/mTOR activation, and this was associated with significant poorer OS [104]. Poor prognosis in AML patients with constitutive PI3K/Akt/mTOR signaling could be related to the fact that this pathway is associated with chemoresistance, which contributes to the short-term survival in AML [25,105,106]. However, no correlation was shown to exist between PI3K/Akt/mTOR activity and a particular AML subtype, cytogenetic abnormality, or etiology of the disease [107,108].…”
Section: Constitutive Pi3k/akt/mtor Activation In Amlmentioning
confidence: 99%
See 1 more Smart Citation
“…About 50-80% of patients with AML display constitutive PI3K/Akt/mTOR activation, and this was associated with significant poorer OS [104]. Poor prognosis in AML patients with constitutive PI3K/Akt/mTOR signaling could be related to the fact that this pathway is associated with chemoresistance, which contributes to the short-term survival in AML [25,105,106]. However, no correlation was shown to exist between PI3K/Akt/mTOR activity and a particular AML subtype, cytogenetic abnormality, or etiology of the disease [107,108].…”
Section: Constitutive Pi3k/akt/mtor Activation In Amlmentioning
confidence: 99%
“…Treatment of AML patient samples with PI3K inhibitor LY294002 displayed inhibited Akt phosphorylation and NF-κB DNA-binding activity [22]. Furthermore, PI3K/Akt/mTOR inhibition induced apoptosis in primary AML cells and potentiated response to cytotoxic chemotherapy, while sparing normal HSC function, [23][24][25][26]. The LSC population was targeted by PI3K-directed therapies demonstrated by reduced engraftment ability of these cells in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice [23,24].…”
Section: Introductionmentioning
confidence: 99%
“…Targeted inhibition of mTOR kinase can be used as a potential strategy for the treatment of AML, and may also affect the resistance of AML to chemotherapy drugs [45]. Targeted inhibition of mTOR in AML cells can signi cantly reduce cell metabolic activity, block the cell cycle, and induce apoptosis, which may be a potential therapeutic strategy for AML [46][47][48][49]. In the process of tumor cell development and development, EMT will also cause tumor cells to lose some of the characteristics of epithelial cells to obtain some of the characteristics of interstitial cells, and also allow tumor cells to acquire stronger invasion and detachment capabilities.…”
Section: Discussionmentioning
confidence: 99%
“…In particular, PTEN converts PtdIns(3,4,5)P3 into PtdIns(4,5)P2, directly reversing the effects of PI3K. Thus, PTEN inactivation leads to PtdIns(3,4,5)P3 accumulation and, consequently, to the hyperactivation of Akt [13][14][15]. The PI3K/Akt pathway is involved with mTOR signaling, which is downstream and represents one of the frequently deregulated pathways in cancer cells, and one of the most important targets of new cancer therapies [118].…”
Section: Pi3k/akt/mtormentioning
confidence: 99%
“…Several stimuli, including a range of growth factors and mitogens, activate cell surface tyrosine kinase receptors, which in turn determine the activation of PI3K. For further activation, Akt is phosphorylated by mammalian target of rapamycin (mTOR) to regulate cell metabolism and differentiation [13][14][15]. In addition, the PI3K/Akt/mTOR pathway has some overlapped functions with PLCs and PKC [16].…”
Section: Introductionmentioning
confidence: 99%