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

Alessio Terenzi, Rostyslav R. Panchuk, Petra Heffeter, Alessio Terenzi, Iryna J. Kril, Walter Berger, Theresa Downey, Rostyslav S. Stoika, Lilya V. Lehka, Sushilla Van Schoonhoven, Amit K. Jha, Irene Herbacek, Bohdan P. Matselyukh, Jürgen Rohr

Risultato della ricerca: Articlepeer review

13 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)134-147
Numero di pagine14
RivistaFREE RADICAL BIOLOGY & MEDICINE
Volume106
Stato di pubblicazionePublished - 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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