The potential of arsenic trioxide in the treatment of malignant disease: past, present, and future

Evens, Andrew M.; Tallman, Martin S.; Gartenhaus, Ronald B.

doi:10.1016/j.leukres.2004.01.011

Cited by 167 publications

(139 citation statements)

References 109 publications

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Section: Introductionmentioning

confidence: 99%

“…In more recent times EhrlichЈs discovery of the antisyphilitic drug arsphenamine (also known as salvarsan) by systematic chemical modification of arsenic derivatives marked the beginning of modern pharmaceutical research. Arsenic trioxide (ATO) is used today in cancer treatment (Evens et al, 2004;Lu et al, 2007;Wang and Chen, 2008).Exposure to arsenic evokes a broad spectrum of cellular reactions in Saccharomyces cerevisiae Haugen et al, 2004;Jin, 2008;Thorsen et al, 2007) and in higher eukaryotes (Salnikow and Zhitkovich, 2008). A number of mechanisms exist for detoxification, probably because arsenic has always been widespread in the environment.…”

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confidence: 99%

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Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Hosiner

Lempiäinen

Reiter³

et al. 2009

MBoC

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The conserved Target Of Rapamycin (TOR) growth control signaling pathway is a major regulator of genes required for protein synthesis. The ubiquitous toxic metalloid arsenic, as well as mercury and nickel, are shown here to efficiently inhibit the rapamycin-sensitive TORC1 (TOR complex 1) protein kinase. This rapid inhibition of the TORC1 kinase is demonstrated in vivo by the dephosphorylation and inactivation of its downstream effector, the yeast S6 kinase homolog Sch9. Arsenic, mercury, and nickel cause reduction of transcription of ribosome biogenesis genes, which are under the control of Sfp1, a TORC1-regulated transcriptional activator. We report that arsenic stress deactivates Sfp1 as it becomes dephosphorylated, dissociates from chromatin, and exits the nucleus. Curiously, whereas loss of SFP1 function leads to increased arsenic resistance, absence of TOR1 or SCH9 has the opposite effect suggesting that TORC1 has a role beyond down-regulation of Sfp1. Indeed, we show that arsenic activates the transcription factors Msn2 and Msn4 both of which are targets of TORC1 and protein kinase A (PKA). In contrast to TORC1, PKA activity is not repressed during acute arsenic stress. A normal level of PKA activity might serve to dampen the stress response since hyperactive Msn2 will decrease arsenic tolerance. Thus arsenic toxicity in yeast might be determined by the balance between chronic activation of general stress factors in combination with lowered TORC1 kinase activity. INTRODUCTIONThe transition metal arsenic has a long history of human exploitation as both a poison and a medicine. In more recent times EhrlichЈs discovery of the antisyphilitic drug arsphenamine (also known as salvarsan) by systematic chemical modification of arsenic derivatives marked the beginning of modern pharmaceutical research. Arsenic trioxide (ATO) is used today in cancer treatment (Evens et al., 2004;Lu et al., 2007;Wang and Chen, 2008).Exposure to arsenic evokes a broad spectrum of cellular reactions in Saccharomyces cerevisiae Haugen et al., 2004;Jin, 2008;Thorsen et al., 2007) and in higher eukaryotes (Salnikow and Zhitkovich, 2008). A number of mechanisms exist for detoxification, probably because arsenic has always been widespread in the environment. These involve reduction of influx through the aquaglyceroporin Fps1p Thorsen et al., 2006); sequestration into the vacuole in the form of glutathione conjugates, metallothionein, and other metal/protein complexes; and active extrusion (Ghosh et al., 1999). In yeast, genome-wide analysis of the transcription patterns in response to arsenic revealed a complex network of transcription factors controlling the expression of several hundred genes (Haugen et al., 2004;Wysocki et al., 2004;Thorsen et al., 2007). Mitogen-activated protein kinases mediate protective responses involving AP-1-and AP-1-like transcription factors in higher eukaryotes and in fungi (Cavigelli et al., 1996;Rodriguez-Gabriel and Russell, 2005;Thorsen et al., 2006).The mechanisms by which arsenic might influence signalin...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Hosiner

Lempiäinen

Reiter³

et al. 2009

MBoC

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“…Whereas acute exposure to inorganic arsenic in humans results in cardiac failure, peripheral neuropathy, anemia, leucopenia, and death, chronic arsenic exposure can cause a range of cancers (particularly of the skin, lung, bladder, and liver) as well as liver injury, neuropathy, cardiovascular lesions, ovarian dysfunction, aberrant embryo development, and postnatal growth retardation (4, 6 -10). Interestingly, arsenic-containing compounds have proven to be effective as therapeutic agents in treating cancer such as leukemia (11), chronic inflammatory disease such as psoriasis (12), and parasitic infection such as sleeping sickness (13,14). Although chemical interaction with protein thiol groups and generation of reactive oxygen species have been implicated in the actions of arsenic, the exact molecular targets and signaling pathways that account for most of the biological effects of arsenic remain unknown.…”

mentioning

confidence: 99%

Arsenic Induces NAD(P)H-quinone Oxidoreductase I by Disrupting the Nrf2·Keap1·Cul3 Complex and Recruiting Nrf2·Maf to the Antioxidant Response Element Enhancer

Chen

Lin

et al. 2006

Journal of Biological Chemistry

153

147

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The ubiquitous toxic metalloid arsenic elicits pleiotropic adverse and adaptive responses in mammalian species. The biological targets of arsenic are largely unknown at present. We analyzed the signaling pathway for induction of detoxification gene NAD(P)H-quinone oxidoreductase (Nqo1) by arsenic. Genetic and biochemical evidence revealed that induction required cap 'n' collar basic leucine zipper transcription factor Nrf2 and the antioxidant response element (ARE) of Nqo1. Arsenic stabilized Nrf2 protein, extending the t1 ⁄ 2 of Nrf2 from 21 to 200 min by inhibiting the Keap1⅐Cul3-dependent ubiquitination and proteasomal turnover of Nrf2. Arsenic markedly inhibited the ubiquitination of Nrf2 but did not disrupt the Nrf2⅐Keap1⅐Cul3 association in the cytoplasm. In the nucleus, arsenic, but not phenolic antioxidant tert-butylhydroquinone, dissociated Nrf2 from Keap1 and Cul3 followed by dimerization of Nrf2 with a Maf protein (Maf G/Maf K). Chromatin immunoprecipitation demonstrated that Nrf2 and Maf associated with the endogenous Nqo1 ARE enhancer constitutively. Arsenic substantially increased the ARE occupancy by Nrf2 and Maf. In addition, Keap1 was shown to be ubiquitinated in the cytoplasm and deubiquitinated in the nucleus in the presence of arsenic without changing the protein level, implicating nuclear-cytoplasmic recycling of Keap1. Our data reveal that arsenic activates the Nrf2/Keap1 signaling pathway through a distinct mechanism from that by antioxidants and suggest an "onswitch" model of Nqo1 transcription in which the binding of Nrf2⅐Maf to ARE controls both the basal and inducible expression of Nqo1.Environmental toxic metal arsenic, which originates from both geochemical and anthropogenic activities, is a ubiquitous contaminant and an established human carcinogen (1, 2). Arsenic has become a major public health concern worldwide because millions of people are at risk of drinking water contaminated with arsenic that has been associated with multiple human diseases or lesions (3-5). The anthropogenic sources of arsenic contaminating soil and water include mining, metallurgical activities, and manufacture and agricultural use of pesticides and herbicides. Arsenic causes a spectrum of adverse responses in many species. Whereas acute exposure to inorganic arsenic in humans results in cardiac failure, peripheral neuropathy, anemia, leucopenia, and death, chronic arsenic exposure can cause a range of cancers (particularly of the skin, lung, bladder, and liver) as well as liver injury, neuropathy, cardiovascular lesions, ovarian dysfunction, aberrant embryo development, and postnatal growth retardation (4, 6 -10). Interestingly, arsenic-containing compounds have proven to be effective as therapeutic agents in treating cancer such as leukemia (11), chronic inflammatory disease such as psoriasis (12), and parasitic infection such as sleeping sickness (13, 14). Although chemical interaction with protein thiol groups and generation of reactive oxygen species have been implicated in the actions of arsenic, the...

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“…18 These effects are dosedependent in vitro, with induction of apoptosis via both PML-RARα-dependent and -independent mechanisms at high concentrations. 19 PML-RARα-independent mechanisms have the potential for off-target effects that may underlie the delay in normal hematopoietic recovery seen in our study. For example, in APL NB4 cells in vitro, this includes a H 2 O 2 -dependent pathway that results from sensitivity of the intracellular glutathione redox system to ATO.…”

Section: Clinical Outcomesmentioning

confidence: 65%

Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis

Mannis

Logan

Leavitt

et al. 2014

Bone Marrow Transplant

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A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naïve patients; P o0.001). Compared with ATO-naïve patients, ATO-treated patients experienced significantly longer times to ANC recovery (median 12 days vs 9 days, P o 0.001). In multivariate analysis, the only significant independent predictor of delayed neutrophil engraftment was prior treatment with ATO (hazard ratio 4.87; P o 0.001). Of the available stem cell aliquots from APL patients, the median viable post-thaw CD34+ cell recovery was significantly lower than that of cryopreserved autologous stem cell products from patients with non-APL AML. Our findings suggest that ATO exposure prior to CD34+ cell harvest has deleterious effects on hematopoietic recovery after autologous HSCT.

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The potential of arsenic trioxide in the treatment of malignant disease: past, present, and future

Cited by 167 publications

References 109 publications

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Arsenic Induces NAD(P)H-quinone Oxidoreductase I by Disrupting the Nrf2·Keap1·Cul3 Complex and Recruiting Nrf2·Maf to the Antioxidant Response Element Enhancer

Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis

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