Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells

Yang, James Chih‐Hsin; Kuo, Min-Liang; Chen, JC; Yc, Chen

doi:10.1038/sj.bjc.6690766

Cited by 115 publications

(86 citation statements)

References 11 publications

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“…In fact, production of ROS can be suppressed by Bcl-x L and inhibition of glutathione synthesis by BSO enhanced arsenite induced necrotic cell demise as reported previously in arsenite-induced apoptosis Kitamura et al, 2000). Functional data corroborate that generation of ROS is a key feature of arsenite-mediated cell death (Wang et al, 1996;Chen et al, 1998;Jing et al, 1999;Yang et al, 1999). Oxidative stress induces cell death through mitochondria, where the pursuit of an apoptotic or a necrotic pathway depends on the strength of the insult and the availability of functional caspases (Fernandes and Cotter, 1994;Fiers et al, 1999).…”

Section: Discussionsupporting

confidence: 68%

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

et al. 2005

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Cell death is generally believed to occur either by accidental, lytic necrosis or by programmed cell death, that is, apoptosis. The initiation and execution of cell death, however, is far more complex and includes pathways like caspase-independent apoptosis or actively triggered necrosis. In this study, we investigated the mechanisms of cell death induced by arsenic trioxide (arsenite, As 2 O 3 ), a clinically efficient agent in anticancer therapy. As 2 O 3 -induced cell death coincides with cytochrome c release, facilitates mitochondrial permeability transition and is sensitive to inhibition by Bcl-x L , indicating that cell demise is regulated through the mitochondrial apoptosis pathway. Nevertheless, only little caspase-3 activation was observed and As 2 O 3 -induced cell death was only weakly obstructed by the broad spectrum caspase inhibitor z-VAD-fmk. Moreover, disruption of caspase-9 or -2 failed to decrease the amount of As 2 O 3 -mediated cell death. Interestingly, As 2 O 3 -induced cell death had a predominantly necrosis-like phenotype as assessed by Annexin-V/propidium iodide staining and LDH release. Finally, blocking glutathione synthetase by buthionine sulfoximine enhanced the As 2 O 3 -mediated necrosis-like cell death without increasing caspase-3 cleavage. As 2 O 3 does, however, not directly inhibit caspases, but appears to interfere with caspase activation. Altogether, our data clearly delineate a mode of As 2 O 3 -triggered cell death that differs considerably from that induced by conventional anticancer drugs. These findings may explain the capability of As 2 O 3 to efficiently kill even chemoresistant tumor cells with disturbed apoptosis signaling and caspase activation, a frequent finding in malignancy.

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Section: Discussionsupporting

confidence: 68%

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

et al. 2005

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“…Several in vitro experiments have already examined the efficacy of the combined treatment with As 2 O 3 plus BSO, although the approach is experimental, not therapeutic. 13,18,19 However, to our knowledge, this is the first in vivo study that investigated the combination therapy with As 2 O 3 plus BSO. Our in vivo study showed that this combination induced tumor growth inhibition in both primary and metastatic lesions, and that this combination therapy prolonged survival rate significantly compared with the control or As 2 O 3 treatment alone.…”

Section: Discussionmentioning

confidence: 99%

Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine

et al. 2004

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Clinical application of anticancer agents has been often hampered by toxicity against normal cells, so the achievement of their cancer-specific action is still one of the major challenges to be addressed. Previously, we reported that arsenic trioxide (As 2 O 3 ) could be a promising new drug against not only leukemia but also solid tumors. The cytotoxicity of As 2 O 3 occurred through the generation of reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of As 2 O 3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination therapy of As 2 O 3 with L-buthionine-sulfoximine (BSO), which inhibits a critical step in glutathione synthesis, effectively enhanced in vitro growth inhibition effect of As 2 O 3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and kidney cancers, compared with As 2 O 3 treatment alone. Furthermore, this combination enhanced cytotoxicity to cell lines from prostate cancer with less toxicity to those from normal prostate. In vitro cytotoxic assay using ROSrelated compounds demonstrated that hydrogen peroxide (H 2 O 2 ) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of As 2 O 3 and BSO blocked H 2 O 2 -scavenging systems including glutathione, catalase, and glutathione peroxidase, and that the degree of this blockade was well correlated with intracellular ROS levels and sensitivity to this treatment. Finally, the effectiveness of the combination therapy of As 2 O 3 with BSO was demonstrated with an orthotopic model of prostate cancer metastasis. We propose that the combination therapy of As 2 O 3 with BSO is a valid means of blockade of H 2 O 2 -scavenging system, and that the combination of a ROSgenerating agent with an inhibitor of major scavenging systems is effective in terms of both efficacy and selectivity. Furthermore, because the effective doses of both compounds are within clinically achievable range, this report will lead to immediate benefit for the development of a new cancer therapy.

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“…The cellular glutathione and MRP levels are reported with their relationship to ATO-resistance. 10, 14 Walter et al 15 reported that MRP1 might attenuate the susceptibility to GO, although by a smaller degree than P-gp. We could not find an obvious relationship between MRP1 and GO-resistance.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells

et al. 2005

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Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells

Cited by 115 publications

References 11 publications

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine

Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells

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