The novel arsenical Darinaparsin circumvents BRG1-dependent, HO-1-mediated cytoprotection in leukemic cells

Garnier, Nicolas; Petruccelli, Luca A.; Molina, Manuel Flores; Kourelis, Maria; Kwan, Stanley; Diaz, Zuanel; Schipper, Hyman M.; Gupta, Abhishek; Rincón, Sonia V. del; Mann, Koren K.; Miller, Wilson H.

doi:10.1038/leu.2013.54

Cited by 16 publications

(16 citation statements)

References 39 publications

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“…Two additional transcription factors, Nrf2 and NF-κB, control HO-1 gene and protein expression (Garnier et al 2013; Wang et al 2012; Lim et al 2014). We monitored Nrf2 and phospho-NF-κB p65 (acive form) nuclear protein levels after As exposure of HK-2 cells.…”

Section: Resultsmentioning

confidence: 99%

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

2015

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Our recent study demonstrated that sodium arsenite at a clinically relevant dose induced nephrotoxicity in human renal proximal tubular epithelial cell line HK-2, which could be inhibited by natural product 2,3,5,6-Tetramethylpyrazine (TMP) with antioxidant activity. The present study demonstrated that arsenic exposure resulted in protein and enzymatic induction of heme oxygenase-1 (HO-1) in dose- and time-dependent manners in HK-2 cells. Blocking HO-1enzymatic activity by Zinc protoporphyrin (ZnPP) augmented arsenic-induced apoptosis, ROS production and mitochondrial dysfunction, suggesting a critical role for HO-1 as a renal protectant in this procession. On the other hand, TMP, upstream of HO-1, inhibited arsenic-induced ROS production and ROS-dependent HO-1 expression. TMP also prevented mitochondria dysfunction and suppressed activation of the intrinsic apoptotic pathway in HK-2 cells. Our results revealed that the regulation of arsenic-induced HO-1 expression was performed through multiple ROS-dependent signal pathways and the corresponding transcription factors, including p38 MAPK and JNK (but not ERK), AP-1, Nrf2 and NF-κB. TMP inhibited arsenic-induced activations of JNK, p38 MAPK, ERK, AP-1 and Nrf2 and block HO-1 protein expression. The present study, furthermore, demonstrated arsenic-induced expression of Arsenic response protein 2 (ARS2) that was regulated by p38 MAPK, ERK and NF-κB. To our knowledge, this is the first report showing that ARS2 involved in arsenic-induced nephrotoxicity while TMP pretreatment prevented such an up-regulation of ARS2 in HK-2 cells. Given ARS2 and HO-1 sharing the similar regulation mechanism, we speculated that ARS2 might also mediate cell survival in this procession. In summary, our study highlighted a role of HO-1 in the protection against arsenic-induced cytotoxicity downstream from the primary targets of TMP and further indicated that TMP may be used as a potential therapeutic agent in the treatment of arsenic-induced nephrotoxicity.

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Section: Resultsmentioning

confidence: 99%

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

2015

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“…SLC7A11 has an antioxidant response element in its promoter, and is regulated by the nuclear factor (erythroid-derived 2)-like 2 (NRF2) in response to intracellular ROS (Sasaki et al, 2002;Shih et al, 2003;Wang et al, 2007). ATO and Dar Link between Darinaparsin and Cystine Import induce intracellular ROS production that activates the NRF2 signaling pathway, thereby leading to expression of NRF2 target genes (Diaz et al, 2005;Mann et al, 2009;Garnier et al, 2013). Therefore, we tested the ability of Dar and ATO to induce xCT.…”

Section: Resultsmentioning

confidence: 99%

The Novel Arsenical Darinaparsin Is Transported by Cystine Importing Systems

et al. 2014

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Darinaparsin (Dar; ZIO-101; S-dimethylarsino-glutathione) is a promising novel organic arsenical currently undergoing clinical studies in various malignancies. Dar consists of dimethylarsenic conjugated to glutathione (GSH). Dar induces more intracellular arsenic accumulation and more cell death than the FDAapproved arsenic trioxide (ATO) in vitro, but exhibits less systemic toxicity. Here, we propose a mechanism for Dar import that might explain these characteristics. Structural analysis of Dar suggests a putative breakdown product: dimethylarsinocysteine (DMAC). We show that DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, cell cycle arrest, and cell death. We found that inhibition of g-glutamyltranspeptidase (g-GT) protects human acute promyelocytic leukemia cells (NB4) from Dar, but not from DMAC, suggesting a role for g-GT in the processing of Dar. Overall, our data support a model where Dar, a GSH S-conjugate, is processed at the cell surface by g-GT, leading to formation of DMAC, which is imported via xCT, xAG, or potentially other cystine/cysteine importing systems. Further, we propose that Dar induces its own import via increased xCT expression. These mechanisms may explain the enhanced toxicity of Dar toward cancer cells compared with ATO.

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“…After treatment with compounds for the indicated times, the cells were harvested. Then, cellular and nuclear extracts were prepared and analysed as previously described …”

Section: Methodsmentioning

confidence: 99%

“…Then, cellular and nuclear extracts were prepared and analysed as previously described. 30,31 Cell lysates extracted from tumour tissues from mice in the treatment groups were prepared and analysed as we previously reported. 30…”

Section: Cell Lysates and Western Blot Analysismentioning

confidence: 99%

Simultaneous NF‐κB inhibition and E‐cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo

Zheng

Zhuang

et al. 2014

Intl Journal of Cancer

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Suberoylanilide hydroxamic acid (SAHA) is a promising histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA) and whose clinical application for solid tumours is partially limited by decreased susceptibility in cancer cells due to nuclear factor (NF)-jB activation. As an NF-jB inhibitor, celastrol exhibits potent anticancer effects but has failed to enter clinical trials due to its toxicity. In this report, we demonstrated that the combination of celastrol and SAHA exerted substantial synergistic efficacy against human cancer cells in vitro and in vivo accompanied by enhanced caspasemediated apoptosis. This drug combination inhibited the activation of NF-jB caused by SAHA monotherapy and consequently led to increased apoptosis in cancer cells. Interestingly, E-cadherin was dramatically downregulated in celastrol-resistant cancer cells, and E-cadherin expression was closely related to decreased sensitivity to celastrol. However, our combination treatment significantly augmented the expression of E-cadherin, suggesting that mutual mechanisms contributed to the synergistic anticancer activity. Furthermore, the enhanced anticancer efficacy of celastrol combined with SAHA was validated in a human lung cancer 95-D xenograft model without increased toxicity. Taken together, our data demonstrated the synergistic anticancer effects of celastrol and SAHA due to their reciprocal sensitisation, which was simultaneously regulated by NF-jB and E-cadherin; thus, the combination of celastrol and SAHA was superior to other combination regimens that rely on a single mechanism. Our findings not only open new opportunities for the clinical development of SAHA but should also motivate the clinical investigation of celastrol, which has been hampered by its toxicity.Histone deacetylase (HDAC) activity is associated with cancer cell proliferation, survival and maintenance and thus represents an attractive target for cancer therapy. HDAC inhibition triggers a series of cellular responses that interfere with growth-promoting signals, enhances cellular stress and ultimately leads to cancer cell death.1 Suberoylanilide hydroxamic acid (SAHA) is one of the most promising HDAC inhibitors for the treatment of cancer, and it has been approved by the US Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma.2 In addition, SAHA as a monotherapy or in combination with other chemotherapeutic agents has been used in clinical trials to treat hematologic malignancies and solid tumours, including lung, breast, ovarian and prostate cancers. 3 Moreover, the safety profile of SAHA has been shown to be favourable, particularly compared with traditional cytotoxic chemotherapy, raising the possibility that SAHA may also be a promising drug for the treatment of solid tumours. 2 Nevertheless, early results from a few clinical trials have indicated that SAHA monotherapy has only modest activity

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The novel arsenical Darinaparsin circumvents BRG1-dependent, HO-1-mediated cytoprotection in leukemic cells

Cited by 16 publications

References 39 publications

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

The Novel Arsenical Darinaparsin Is Transported by Cystine Importing Systems

Simultaneous NF‐κB inhibition and E‐cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo

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