|
Cytotoxic effect of PI3Kδ inhibitor in acute promyelocytic leukemia cells
|
M. Dadashi   , D. Bashash |
|
|
| Keywords: Key words: Acute Promyelocytic Leukemia, Inhibition, Apoptosis |
|
|
Full-Text [PDF 2124 kb]
(1297 Downloads)
| Abstract (HTML) (4489 Views)
|
Type of Study: Research |
Subject:
Hematology
Published: 2017/06/19
|
|
|
|
|
|
|
Full-Text: (1602 Views) |
References :
- Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood 2009; 114(25): 5126-35.
- Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet 2013; 381(9865): 484-95.
- Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet 1977; 1(8010):
549-50.
- Thirman MJ, Larson RA. Therapy-related myeloid leukemia. Hematol Oncol Clin North Am 1996; 10(2): 293-320.
- Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 2002; 99(6): 1909-12.
- Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. Oncologist 2001; 6 Suppl 2: 1-2.
- Martelli AM, Nyåkern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C, et al . Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006; 20(6): 911-28.
- Tzenaki N, Papakonstanti EA. p110δ PI3 kinase pathway :emerging roles in cancer. Front Oncol 2013; 3: 40.
- Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011; 117(2): 591-4.
- Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL, et al. PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012; 119(8): 1897-900.
- Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, et al. PI3K/p110δ is a novel therapeutic target in multiple myeloma. Blood 2010; 116(9): 1460-8.
- Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer BA, Liebermann M, et al. Differential Effects of Selective Inhibitors Targeting the PI3K/AKT/mTOR Pathway in Acute Lymphoblastic Leukemia. PLoS One 2013; 8(11): e80070.
- LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA.. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 2008; 11(1-2): 32-50.
- Yang Q, Modi P, Newcomb T, Quéva C, Gandhi V. Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic. Leukemia, and Follicular Lymphoma. Clin Cancer Res 2015; 21(7): 1537-42
- Fransecky L, Mochmann LH, Baldus CD. Outlook on PI3K/AKT/mTOR inhibition in acute leukemia. Mol Cell Ther 2015; 3: 2.
- Rosin NY, Koehrer S, Kim E, O'Brien S, Wierda WG, Thomas DA, et al. In Vitro Effects of PI3Kδ Inhibitor GS-1101 (Cal-101) in Acute Lymphoblastic Leukemia (ALL). Blood 2012; 120(21): 3534.
- Majchrzak A, Witkowska M, Smolewski P. Inhibition of the PI3K/Akt/mTOR Signaling Pathway in Diffuse Large B-Cell Lymphoma: Current Knowledge and Clinical Significance. Molecules 2014; 19(9): 14304-15.
- Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9(1): 47-59.
- Yu J, Zhang L. PUMA, a potent killer with or without p53. Oncogene 2009; 27: 71-83.
- Hofseth LJ, Hussain SP, Harris CC. p53: 25 years after its discovery. Trends Pharmacol Sci 2004; 25(4): 177-81.
- Luo X, He Q, Huang Y, Sheikh MS. Transcriptional upregulation of PUMA modulates endoplasmic reticulum calcium pool depletion-induced apoptosis via Bax activation. Cell Death Differ 2005; 12(10): 1310-8.
- Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci U S A 2003; 100(4): 1931-6.
|
Sci J Iran Blood Transfus Organ 2017; 14(2):126-134
|
Cytotoxic effect of PI3Kδ inhibitor in acute
promyelocytic leukemia cells
Dadashi M.1, Bashash D.1
1Hematology Department, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Abstract
Background and Objectives
PI3K/Akt pathway plays a key role in cell growth and proliferation. Constitutive activation of this pathway is detectable in 50-70% of patients with acute promyelocytic leukemia (APL). Previous studies showed that PI3K activity in APL cells is mainly due to overexpression of p110δ isoform. In an effort to investigate the effect of PI3K inhibition in acute promyelocytic leukemia, APL-derived NB4 cells were subjected to different concentrations of Idelalisib, as a potent p110δ-specific inhibitor.
Materials and Methods
In this experimental study, we examined the effect of Idelalisib on the viability and metabolic activity of NB4 cells. Moreover, flowcytometery and quantitative RQ-PCR were applied to investigate both induction of apoptosis and transcriptional activity of apoptosis-related genes, respectively.
Results
The results revealed that Idelalisib not only decreased cell viability and metabolic activity in a dose- and time-dependent manner, but also induced cell death through the apoptotic pathway in NB4 cells. Our data also delineated that Idelalisib-induced apoptosis was mediated through induction of Bax and PUMA coupled with decreased expression of Mcl-1.
Conclusions
Based on P110δ activity in APL patients and the potent efficacy of Idelalisib in NB4 cells, it is tempting to suggest this inhibitor, as either single agent or in combination with common medications, for the treatment of patients with APL.
Key words: Acute Promyelocytic Leukemia, Inhibition, Apoptosis
Received: 15 Nov 2016
Accepted: 10 Apr 2017
Correspondence: Bashash D., PhD of Hematology & Blood Banking. Assiatant Professor of Hematology Department, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences.
Postal Code: 1971653312, Tehran, Iran. Tel: (+9821) 22721150; Fax: (+9821) 22721150
E-mail:
david_5980@yahoo.com
|
|
| Send email to the article author |
|
|
|
| Add your comments about this article |
|
|
|
|
|
.jpg)
.png)
