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Rapid generation of hydrogen peroxide contributes to the complex cell death induction by the angucycline antibiotic landomycin E

  • Autori: Panchuk R.R.; Lehka L.V.; Terenzi A.; Matselyukh B.P.; Rohr J.; Jha A.K.; Downey T.; Kril I.J.; Herbacek I.; van Schoonhoven S.; Heffeter P.; Stoika R.S.; Berger W.
  • Anno di pubblicazione: 2017
  • Tipologia: Articolo in rivista
  • Parole Chiave: Anticancer drugs; Apoptosis; Hydrogen peroxide; Landomycin E; Multi-drug resistance; N-acetylcysteine; Reactive oxygen species; Superoxide radicals; Acetylcysteine; Aminoglycosides; Antibiotics, Antineoplastic; Apoptosis; Caspase 7; Caspase 9; Doxorubicin; Humans; Hydrogen Peroxide; Jurkat Cells; Leukemia; Mitochondria; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Reactive Oxygen Species; Streptomyces; Superoxides
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Landomycin E (LE) is an angucycline antibiotic produced by Streptomyces globisporus. Previously, we have shown a broad anticancer activity of LE which is, in contrast to the structurally related and clinically used anthracycline doxorubicin (Dx), only mildly affected by multidrug resistance-mediated drug efflux. In the present study, cellular and molecular mechanisms underlying the anticancer activity of landomycin E towards Jurkat T-cell leukemia cells were dissected focusing on the involvement of radical oxygen species (ROS). LE-induced apoptosis distinctly differed in several aspects from the one induced by Dx. Rapid generation of both extracellular and cell-derived hydrogen peroxide already at one hour drug exposure was observed in case of LE but not found before 24 h for Dx. In contrast, Dx but not LE induced production of superoxide radicals. Mitochondrial damage, as revealed by JC-1 staining, was weakly enhanced already at 3 h LE treatment and increased significantly with time. Accordingly, activation of the intrinsic apoptosis pathway initiator caspase-9 was not detectable before 12 h exposure. In contrast, cleavage of the down-stream caspase substrate PARP-1 was clearly induced already at the three hour time point. Out of all caspases tested, only activation of effector caspase-7 was induced at this early time points paralleling the LE-induced oxidative burst. Accordingly, this massive cleavage of caspase-7 at early time points was inhibitable by the radical scavenger N-acetylcysteine (NAC). Additionally, only simultaneous inhibition of multiple caspases reduced LE-induced apoptosis. Specific scavengers of both H2O2 and OH• effectively decreased LE-induced ROS production, but only partially inhibited LE-induced apoptosis. In contrast, NAC efficiently blocked both parameters. Summarizing, rapid H2O2 generation and a complex caspase activation pattern contribute to the antileukemic effects of LE. As superoxide generation is considered as the main cardiotoxic mechanism of Dx, LE might represent a better tolerable drug candidate for further (pre)clinical development.