Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Abstract

B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/ mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G 0 /G 1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

Balaglitazone reverses P-glycoprotein-mediated multidrug resistance via upregulation of PTEN in a PPARγ-dependent manner in leukemia cells

“…7 Studies have shown that resistance to leukemia chemotherapy is correlated with the activation of PI3K/Akt signaling pathway, as manifested by the fact that inhibition of this signaling pathway can reverse MDR and sensitize tumor cells to chemotherapeutics. [7][8][9] Peroxisome proliferator-activated receptors (PPARs) are nuclear steroid receptors that regulate diverse biological processes such as lipid and carbohydrate metabolism, development, differentiation, apoptosis, neoplastic transformation, inflammation, and regeneration. [10][11][12] PPARs form heterodimers with retinoid X receptors (RXRs) and bind to PPAR response elements (PPREs) located in the promoter of target genes to regulate transcription.…”

Antitumor activity of the Ailanthus altissima bark phytochemical ailanthone against breast cancer MCF‑7 cells

“…The role of the PI3K/AKT pathway and its potential as a therapeutic target for tumor treatment has been investigated in preclinical studies into a number of tumor types, including lung, breast and renal cancer, neuroblastoma and glioblastoma. The results of these studies indicate that the PI3K/AKT signaling pathway and those downstream of it are potential targets for therapeutic intervention (38)(39)(40)(41). The PI3K/AKT pathway serves a role in apoptosis, cell cycle progression and tumorigenesis; therefore, we hypothesize that ailanthone-induced apoptosis may also involve the PI3K/AKT pathway, demonstrating that the ailanthone treatment of Huh7 cells resulted in a decrease in the expression of PI3K and AKT phosphorylation at threonine-408 and serine-473.…”

Effects of VBMDMP on the reversal of cisplatin resistance in human lung cancer A549/DDP cells

“…Akt is a main target of PI3K and is closely related to a variety of cell biological behaviors such as metabolism regulation, cell survival and particularly apoptosis (24,25). Activation of key survival signaling molecules such as PI3K/Akt, especially increasing Akt phosphorylation levels, is not only closely related to cancer cell development and apoptosis inhibition but is also a main step leading to multidrug resistance (26,27).…”