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Adv Pharm Bull. 2019;9(3): 470-480.
doi: 10.15171/apb.2019.056
PMID: 31592121
PMCID: PMC6773944
Scopus ID: 85070475117
  Abstract View: 421
  PDF Download: 296

Research Article

Positive Effects of PI3K/Akt Signaling Inhibition on PTEN and P53 in Prevention of Acute Lymphoblastic Leukemia Tumor Cells

Elahe Naderali 1,2 ORCID logo, Behnaz Valipour 1 ORCID logo, Amir Afshin Khaki 2 ORCID logo, Jafar Soleymani Rad 2, Alireza Alihemmati 2 ORCID logo, Mohammad Rahmati 3 ORCID logo, Hojjatollah Nozad Charoudeh 1 * ORCID logo

1 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
2 Department of Anatomical Sciences, Faculty of Medicine, Tabriz university of Medical Sciences, Tabriz, Iran.
3 Department of Clinical Biochemistry Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Abstract

Purpose: The PI3K/Akt signaling pathway regulates cell growth, proliferation and viability in hematopoietic cells. This pathway always dysregulates in acute lymphoblastic leukemia (ALL). PTEN and P53 are tumor suppressor genes correlated with PI3K/Akt signaling pathway, and both have a tight link in regulation of cell proliferation and cell death. In this study, we investigated the effects of dual targeting of PI3K/Akt pathway by combined inhibition with nvp-BKM-120 (PI3K inhibitor) and MK-2206 (Akt inhibitor) in relation with PTEN and P53 on apoptosis and proliferation of leukemia cells.

Methods: Both T and B ALL cell lines were treated with both inhibitors alone or in combination with each other, and induction of apoptosis and inhibition of proliferation were evaluated by flow cytometry. Expression levels of PTEN as well as p53 mRNA and protein were measured by real-time qRT-PCR and western blot, respectively.

Results: We indicated that both inhibitors (BKM-120 and MK-2206) decreased cell viability and increased cytotoxicity in leukemia cells. Reduction in Akt phosphorylation increased PTEN and p53 mRNA and p53 protein level (in PTEN positive versus PTEN negative cell lines). Additionally, both inhibitors, particularly in combination with each other, increased apoptosis (evaluated with Annexin V and caspase 3) and reduced proliferation (Ki67 expression) in leukemia cells. However, administration of IL7 downregulated PTEN and P53 mRNA expression and rescued cancer cells following inhibition of BKM-120 and MK-2206.

Conclusion: This investigation suggested that inhibition of Akt and PI3K could be helpful in leukemia treatment.

Keywords: PI3K/Akt signaling, MK-2206, BKM-120, ALL, PTEN, P53
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Submitted: 19 Dec 2018
Revision: 23 Apr 2019
Accepted: 15 May 2019
ePublished: 01 Aug 2019
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