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

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.

Zebrafish modeling of intestinal injury, bacterial exposures and medications defines epithelial in vivo responses relevant to human inflammatory bowel disease

“…In our study, mesalamine exerts its protective effects only during injury and not during the recovery period following DSS removal. In contrast, 6-mercaptopurine enhances autophagy solely after DSS removal, consistent with prior literature of direct effects of thiopurines in enhancing autophagy (Chaabane and Appell, 2016). While blockade of pro-inflammatory cytokines such as anti-TNF or anti-IL12/23 (Sandborn et al, 2012) represents major mechanisms for treating moderate to severe CD, it is still an open question as to whether management combining pro-inflammatory cytokine blockade (Abraham et al, 2017) with 6-mercaptopurine provides additional benefit (Colombel et al, 2010).…”

Apoptin Regulates Apoptosis and Autophagy by Modulating Reactive Oxygen Species (ROS) Levels in Human Liver Cancer Cells

“…Studies have shown that cellular stress can cause autophagy, which can also lead to apoptosis ( 42 ). The various roles of these two mechanisms can be defined as the following: (i) autophagy can be used as a survival mechanism by limiting stress caused by environmental factors, and maintaining normal cell function to antagonize apoptosis ( 43 ); (ii) autophagy can also act as a promoter of apoptosis by maintaining ATP levels required for ATP-dependent apoptosis ( 44 ); (iii) autophagy can synergize apoptosis by entering into the apoptotic process and modulating caspase activity ( 45 – 47 ); and (iv) autophagy can also act as a “backup mechanism,” involved in the transport of damaged organelles, such as mitochondria (i.e., mitochondrial autophagy) ( 48 – 50 ).…”

6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner

“…Since the castration-resistant prostate cancer cells assayed in this study have decreased BRCA2 levels compared to the normal PNT1A cells, it is possible that reduced repair of 6-TG-induced DSBs by HR contributes to activation of apoptosis in cancer cells. In addition, 6-TG-mediated toxicity in cancer cells has been also associated with mitochondrial-dependent overproduction of ROS [39]. A previous study has shown that prostate cancer cells have higher ROS production compared with normal prostate cells through activation of the extramitochondrial source of ROS generator, NAD(P)H oxidase [40].…”