Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

Schölz, Christian; Richter, Antje; Lehmann, Mario; Schulze‐Osthoff, Klaus; Dörken, Bernd; Daniel, Peter T.

doi:10.1038/sj.onc.1208868

Cited by 35 publications

(17 citation statements)

References 43 publications

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“…Although we also cannot rule out the possibility that other executed caspases such as caspase-6 and caspase-7 are exclusively required for the induction of apoptosis in As4.1 cells, our results suggest that cell death induced by arsenic trioxide or TNF-␣ in As4.1 cells is not dependent on the activation of caspase. In accordance with our results, caspaseindependent death by arsenic trioxide has been reported by other groups (20,35,36). The mechanism by which arsenite induces this caspase-independent death remains enigmatic.…”

Section: Discussionsupporting

confidence: 82%

Arsenic trioxide inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and caspase-independent apoptosis

Han¹,

Kim²,

Kim³

et al. 2007

American Journal of Physiology-Renal Physiology

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We investigated the in vitro effects of arsenic trioxide on cell growth, cell cycle regulation, and apoptosis in As4.1 juxtaglomerular cells. Arsenic trioxide inhibited the growth of As4.1 cells with an IC50of ∼5 μM. Arsenic trioxide induced S phase arrest of the cell cycle and very efficiently stimulated apoptosis in As4.1 cells, as evidenced by flow cytometric detection of sub-G1DNA content, annexin V binding assay, and 4′-6-diamidino-2-phenylindole staining. This apoptotic process was accompanied by the loss of mitochondrial transmembrane potential (ΔΨm), a decrease in Bcl-2, the activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase. However, all of the caspase inhibitors tested in this experiment failed to rescue As4.1 cells from arsenic trioxide-induced cell death in view of sub-G1cells and annexin V positive-staining cells. However, a caspase-8 inhibitor (Z-IETD-FMK) noticeably decreased the loss of ΔΨmin arsenic trioxide-treated cells. When we examined the changes in reactive oxygen species (ROS), H2O2, or O2•−in arsenic trioxide-treated cells, H2O2was significantly decreased and O2•−was increased. In addition, we detected a decreased GSH content in arsenic trioxide-treated cells. Taken together, we have demonstrated that arsenic trioxide as a ROS generator potently inhibited the growth of As4.1 JG cells through S phase arrest of the cell cycle and caspase-independent apoptosis.

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Section: Discussionsupporting

confidence: 82%

Arsenic trioxide inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and caspase-independent apoptosis

Han¹,

Kim²,

Kim³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…Notably, pan-caspase inhibition by the use of zVADfmk almost completely inhibited p14 ARF -induced cell death, indicating an apoptotic mode of cell death execution. This is a relevant point, as recent data on drug-and oncogene-induced cell death propagate a concept of non-apoptotic cell death, that is, by regulated necrosis or autophagy (Zong et al, 2004;Scholz et al, 2005a, b). This does, however, not appear to be the case in the present setting of p14 ARF -induced apoptosis.…”

Section: Discussionmentioning

confidence: 79%

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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In contrast to the initial notion that the biological activity of p14 ARF strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14 ARF mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14 ARF induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9-and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14 ARF -induced apoptosis, suggesting that p14 ARF -induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14 ARF -induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wildtype HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14 ARF -induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14 ARF expression. These data indicate that p14 ARF triggers apoptosis via a Bax/Bakdependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14 ARF -induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bakindependent mechanism.

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“…Interestingly, in these cells, ATO was found to activate both the intrinsic and extrinsic apoptosis pathways as shown by activation of caspase-9 and caspase-8, respectively (Wu et al, 2010). However, the proapoptotic effect of ATO may, under other circumstances, rely on the intrinsic pathway because cell death can occur via an intrinsic Bcl-2-regulated route in acute promyelocitic leukemia cells (Scholz et al, 2005). In the present article, the observation of caspase-8 activation by ATO supports an involvement of the extrinsic pathway.…”

Section: Tablementioning

confidence: 99%

Improved Apoptotic Cell Death in Drug-Resistant Non–Small-Cell Lung Cancer Cells by Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Based Treatment

Gatti

Cossa

Tinelli

et al. 2013

J Pharmacol Exp Ther

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Since response to platinum-based therapy in non-small-cell lung cancer (NSCLC) is poor, the present study was designed to rationally identify novel drug combinations in cell models including the A549 cell line and the cisplatin-resistant subline A549/Pt, characterized by reduced sensitivity to cisplatin-induced apoptosis and by upregulation of efflux transporters of the ATP binding cassette (ABC) superfamily. Given the molecular features of these cells, we focused on compounds triggering apoptosis through different mechanisms, such as the mitochondria-targeting drug arsenic trioxide and the phenanthridine analog sanguinarine, which induce apoptosis through the extrinsic pathway. Sanguinarine, not recognized by ABC transporters, could overcome cisplatin resistance and, when used in combination with arsenic trioxide, was synergistic in A549 and A549/Pt cells. The arsenic trioxide/sanguinarine cotreatment upregulated genes implicated in apoptosis activation through the extrinsic pathway. Drug combination experiments indicated that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment improved arsenic trioxide/sanguinarine efficacy, a feature associated with a striking apoptosis induction, particularly in the cisplatin-resistant variant. Thus, a synergistic interaction between sanguinarine and arsenic trioxide could be obtained independent of relative cell sensitivity to arsenic trioxide, and an enhanced apoptosis induction could be achieved in combination with TRAIL through modulation of the extrinsic apoptotic pathway. Antitumor activity studies supported the interest of drug combinations including TRAIL in NSCLC, indicating that drug-resistant NSCLC cells can efficiently be killed by the combination of proapoptotic agents. Our results suggest that the molecular changes occurring in treated cells may be exploited to rationally hit surviving cells.

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Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

Cited by 35 publications

References 43 publications

Arsenic trioxide inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and caspase-independent apoptosis

Arsenic trioxide inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and caspase-independent apoptosis

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

Improved Apoptotic Cell Death in Drug-Resistant Non–Small-Cell Lung Cancer Cells by Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Based Treatment

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