Oncotarget

Research Papers:

Interconnections between apoptotic and autophagic pathways during thiopurine-induced toxicity in cancer cells: the role of reactive oxygen species

Wiem Chaabane and Malin Lindqvist Appell _

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Oncotarget. 2016; 7:75616-75634. https://doi.org/10.18632/oncotarget.12313

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Abstract

Wiem Chaabane1, Malin Lindqvist Appell1

1Division of Drug Research, Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden

Correspondence to:

Malin Lindqvist Appell, email: Malin.lindqvist.appell@liu.se

Wiem Chaabane, email: wiemchaabane27@hotmail.fr

Keywords: 6-thioguanine, 6-mercaptopurine, azathioprine, autophagy, apoptosis

Received: May 26, 2016     Accepted: September 15, 2016     Published: September 28, 2016

ABSTRACT

Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are a class of genotoxic drugs extensively used in the treatment of various illnesses including leukemia. Their underlying molecular mechanism of action involves the activation of apoptosis and autophagy but remains widely unclear. Here we present evidence that autophagy induction by thiopurines is a survival mechanism that antagonizes apoptosis and is involved in degrading damaged mitochondria through mitophagy. On the other hand, apoptosis is the main cell death mechanism by thiopurines as its inhibition prohibited cell death. Thus a tight interplay between apoptosis and autophagy controls cell fate in response to thiopurine treatment. Moreover, thiopurines disrupt mitochondrial function and induce a loss of the mitochondrial transmembrane potential. The involvement of the mitochondrial pathway in thiopurine-induced apoptosis was further confirmed by increased formation of reactive oxygen species (ROS). Inhibiting oxidative stress protected the cells from thiopurine-induced cell death and ROS scavenging prohibited autophagy induction by thiopurines. Our data indicate that the anticarcinogenic effects of thiopurines are mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.


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