Minocycline induces apoptosis in acute lymphoblastic leukemia Jurkat cells

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 H2O2-mediated signaling pathway. Indeed, H2O2 serves as a signaling molecule, thus triggering a molecular cascade involving the oxidation of the DJ-1 cysteine106-thiol residue into DJ-1 cysteine106-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.