Cannabinoid CP55940 selectively induces apoptosis in Jurkat cells and in ex vivo T-cell acute lymphoblastic leukemia through H2O2 signaling mechanism. (August 2020)

• Record Type: Journal Article
• Authors: Soto-Mercado, Viviana; Mendivil-Perez, Miguel; Jimenez-Del-Rio, Marlene; Fox, Javier E; Velez-Pardo, Carlos
• Is Part Of: Leukemia research. Volume 95(2020)
• Publication Date: 2020-08
• Subjects: Apoptosis -- Cannabinoid -- CP55940 -- Oxidative stress -- T-acute lymphoblastic leukemia; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2020.106389
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: CP55940 triggers apoptosis in Jurkat cells via oxidative stress mechanism. CP55940 turn down the mitochondria membrane potential in Jurkat cells. CP55940-induced apoptosis involves P53, c-JUN, PUMA, BAX, Parkin and PINK1. CP55940 is innocuous to peripheral blood lymphocytes. CP55940 induces apoptosis in ex vivo T-cell ALL via caspase-3 dependent pathway. Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous malignant hematological disorder arising from T-cell progenitors. This study was aimed to evaluate the cytotoxic effect of CP55940 on human peripheral blood lymphocytes (PBL) and on T-ALL cells (Jurkat). PBL and Jurkat cells were treated with CP55940 (0−20 μM), and morphological changes in the cell nucleus/ DNA, mitochondrial membrane potential (ΔΨm), and intracellular reactive oxygen species levels were determined by fluorescence microscopy and flow cytometry. Cellular apoptosis markers were also evaluated by western blotting, pharmacological inhibition and immunofluorescence. CP55940 induced apoptotic cell death in Jurkat cells, but not in PBL, in a dose–response manner with increasing fragmentation of DNA, arrest of cell cycle and damage of ΔΨm. CP55940 increased dichlorofluorescein fluorescence (DCF) intensity, increased DJ-1 Cys 106 - sulfonate, a marker of intracellular stress, induced the up-regulation of p53 and phosphorylation of transcription factor c-JUN. It increased the expression of BAX and PUMA, up-regulated mitochondrial proteins PINK1 and Parkin, and activated CASPASE-3. Antioxidant NAC, pifithrin-α, and SP600125 blocked CP55940 deleterious effect on Jurkat cells. However, the potent and highly specific cannabinoid CB1 and CB2 receptor inverse agonist SR141716 and SR144528 were unable to blunt CP55940-induced apoptosis in Jurkat cells. Conclusively CP55940 provokes cell death in Jurkat through CBR-independent mechanism. Interestingly, CP55940 was also cytotoxic to ex vivo T-ALL cells from chemotherapy-resistant pediatric patients. In conclusion, CP55940 selectively induces apoptosis in Jurkat cells through a H2 O2 -mediated signaling pathway. Our findings support the use of cannabinoids as a potential treatment for T-ALL cells.