Minocycline induces apoptosis in acute lymphoblastic leukemia Jurkat cells. (August 2018)

• Record Type: Journal Article
• Authors: Ruiz-Moreno, Cristian; Velez-Pardo, Carlos; Jimenez-Del-Rio, Marlene
• Is Part Of: Toxicology in vitro. Volume 50(2018)
• Page Start: 336
• Page End: 346
• Publication Date: 2018-08
• Subjects: ALL acute lymphoblastic leukemia -- AIF apoptosis-inducing factor -- BAX Bcl-2 associated X -- DCFH-DA dichlorodihydrofluorescein diacetate -- DCF dichlorofluorescein -- H2O2 hydrogen peroxide -- hPBCLs human peripheral blood lymphocyte cells -- ΔΨm mitochondria membrane potential -- Mino minocycline -- NF-κB nuclear factor kappaB -- NAC N-acetyl-cysteine -- PINK1 PTEN-induced putative kinase 1 -- PUMA p53 upregulated modulator of apoptosis; Acute lymphoblastic leukemia -- Apoptosis -- Jurkat -- Minocycline -- Leukemia -- Signaling; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2018.03.012
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Acute lymphoblastic leukemia (ALL) is still an incurable hematologic malignant disorder. Therefore, novel therapeutic approaches are urgently required. In this study, we tested the pro-apoptotic properties of minocycline (Mino) in human peripheral blood lymphocyte cells (hPBLCs) and Jurkat cells (clone E6-1). hPBLCs and Jurkat cells were exposed to increasing concentrations of minocycline (Mino; 10–200 μM). We found that Mino induces apoptosis in Jurkat cells through an H2 O2 -mediated signaling pathway. Indeed, H2 O2 serves as a signaling molecule, thus triggering a molecular cascade involving the oxidation of the DJ-1 cysteine 106 -thiol residue into DJ-1 cysteine 106 -sulfonic acid; activation of transcription factors NF-kappaB, P53 and c-JUN; up-regulation of pro-apoptotic proteins BAX/PUMA and proteins involved in the maintenance of mitochondrial function PINK1/PARKIN; and loss of mitochondrial membrane potential and activation of CASPASE-3/AIF, which are responsible for nuclear fragmentation, demonstrated by fluorescence microscopy, flow cytometry and Western blot analysis. Interestingly, Mino induced none of the aforementioned oxidative stress and/or apoptosis markers in hPBLCs. We report for the first time that minocycline, a second-generation, semi-synthetic tetracycline derivative, selectively induces apoptosis in Jurkat cells through an oxidative stress-mediated mechanism. Additionally, since Mino has well-established clinical pharmacokinetic and pharmacodynamic properties, we propose that this tetracycline is a promising anti-leukemic drug against ALL. Graphical abstract: Unlabelled Image Highlights: Mino cycline induces apoptosis in Jurkat cells via oxidative stress mechanism. Mino cycline induces apoptosis dependent on activation of transcription factors. Mino cycline induces apoptosis dependent on pro-apoptotic proteins BAX/PUMA. Drug repurposing of minocycline against acute lymphoblastic leukemia. Mino cycline is harmless to human peripheral blood lymphocyte cells.