Nrf2 activation ameliorates cytotoxic effects of arsenic trioxide in acute promyelocytic leukemia cells through increased glutathione levels and arsenic efflux from cells

Nishimoto, Shoichi; Suzuki, Toshihiro; Koike, Sachiko; Yuan, Bo; Takagi, Norio; Ogasawara, Yuki

doi:10.1016/j.taap.2016.06.017

Cited by 21 publications

(15 citation statements)

References 42 publications

(53 reference statements)

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“…HO‐1 is one of the NRF2‐targeted genes , which is also responsible for the resistance to chemotherapeutic agents in AML cells . More recently, it has been shown that the anticancer effects of As 2 O 3 are attenuated by the induction of HO‐1 resulting from pretreatment with an NRF2 inducer . Therefore, we discover a new pro‐leukemogenic axis exploited by the short isoform of PR through its synergistic cooperation with NRF2 transcriptional factor.…”

Section: Discussionmentioning

confidence: 98%

The short isoform of PML‐RARα activates the NRF2/HO‐1 pathway through a direct interaction with NRF2

Wang

et al. 2017

FEBS Letters

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The NF-E2 p45-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 signaling pathway plays an important role in cytoprotection. In acute promyelocytic leukemia, fusion of the promyelocytic leukemia protein (PML) with retinoic acid receptor alpha (RARα) results in an oncogene, PML-RARα (PR). Although previous studies have shown that both RARα and PML inhibit NRF2 activity, how PR regulates NRF2 has not been reported. Here, we discovered that PR-S, the short isoform of PR, potentiates NRF2 activity in a tert-butylhydroquinone (tBHQ) concentration-dependent manner. Furthermore, PR-S colocalized with NRF2 in HeLa and HEK293T cells. The association of PR-S and NRF2 is mediated by the DNA-binding domains of RARα and the Neh7 domain of NRF2. Our results define a novel function of PR-S as a NRF2-transcriptional co-activator.

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Section: Discussionmentioning

confidence: 98%

The short isoform of PML‐RARα activates the NRF2/HO‐1 pathway through a direct interaction with NRF2

Wang

et al. 2017

FEBS Letters

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“…In HL-60 cells, CA enhanced expression of the vitamin D and retinoic acid receptors thus, enhancing the sensitivity of cells to 1,25D [71], and enhanced expression of cell cycle regulators p21 Waf1 , p27 Kip1 which may have tumor suppressor functions [72]. Carnosic acid also increased levels of the antioxidant GSH and phase II enzyme NADP(H)-quinone reductase which help protect cells from chemically-induced carcinogenesis, and enhanced signaling through MAPK pathways including ERK and JNK which are involved in the proliferation and differentiation of cells [40,73,74,75,79]. In K562 leukemia cells CA inhibited cell viability and sensitized resistant cells to adriamycin, a chemotherapeutic agent [30,80].…”

Section: Anticancer Effects Of Carnosic Acid (Ca): In Vitro Studiesmentioning

confidence: 99%

“…Similarly, CA enhanced the activity of doxercaliferol, an agent which helps prevent the common problem of calcification associated with administration of vitamin D derivatives such as 1,25D, and decreased levels of microRNA181a which are linked to cell proliferation [81]. Antioxidant effects were also produced by CA in U937, HL-60 and NB4 leukemic cells which exhibited increased GSH and NADPH levels and CA ameliorated arsenic trioxide-induced cytotoxic effects [79]. Activation of the Nrf2/ARE signalling pathway which can alter cell survival was also seen [77,79].…”

Section: Anticancer Effects Of Carnosic Acid (Ca): In Vitro Studiesmentioning

confidence: 99%

“…Antioxidant effects were also produced by CA in U937, HL-60 and NB4 leukemic cells which exhibited increased GSH and NADPH levels and CA ameliorated arsenic trioxide-induced cytotoxic effects [79]. Activation of the Nrf2/ARE signalling pathway which can alter cell survival was also seen [77,79]. The authors suggest that the Nrf2/ARE pathway likely plays an important role in the cooperative induction of leukemia cell differentiation by 1,25D and CA [77].…”

Section: Anticancer Effects Of Carnosic Acid (Ca): In Vitro Studiesmentioning

confidence: 99%

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Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols

2016

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Cancer cells display enhanced growth rates and a resistance to apoptosis. The ability of cancer cells to evade homeostasis and proliferate uncontrollably while avoiding programmed cell death/apoptosis is acquired through mutations to key signaling molecules, which regulate pathways involved in cell proliferation and survival. Compounds of plant origin, including food components, have attracted scientific attention for use as agents for cancer prevention and treatment. The exploration into natural products offers great opportunity to evaluate new anticancer agents as well as understand novel and potentially relevant mechanisms of action. Rosemary extract has been reported to have antioxidant, anti-inflammatory, antidiabetic and anticancer properties. Rosemary extract contains many polyphenols with carnosic acid and rosmarinic acid found in highest concentrations. The present review summarizes the existing in vitro and in vivo studies focusing on the anticancer effects of rosemary extract and the rosemary extract polyphenols carnosic acid and rosmarinic acid, and their effects on key signaling molecules.

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“…1). Although NRF2 pathway activation by iAs has been reported in various cell types [28][29][30], however, the experimental data in vivo are very limited and not fully elucidated in humans. Several in vitro experiments have indicated that the TRX system is involved in As-induced cell responses.…”

Section: As-mediated Activation Of Nrf2-keap1 Antioxidant Pathwaymentioning

confidence: 99%

Effect of arsenic exposure on Nrf2-Keap1 pathway and epigenetic modification

et al. 2016

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Arsenic (As) is a known toxic element and carcinogen. Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidant genes in response to redox stress. To explore associations between As level and NRF2-regulated cytoprotective genes expression, an observational study was conducted in a population of 61 occupationally exposed men with median (Me) age 50 years (interquartile range (IQR) 42-54) and in a control group of 52 men aged 40 (IQR 31-51.5) without occupational exposure. NRF2, KEAP1, GSTP1, HMOX1, NQO1, PRDX1, and TXNRD1 transcript levels were determined by means of quantitative real-time PCR along with the gene expression, methylation of NRF2 and KEAP1, as well as global DNA methylation were assessed. The median urine As tot. level in the exposed and control group was found to be 21.8 μg/g creat. (IQR 15.5-39.8 μg/g creat.) and 3.8 μg/g creat. (IQR 2.5-9.3) (p < 0.001). Global DNA methylation was significantly higher in occupationally exposed workers than in controls (Me 14.1 (IQR 9.5-18.1) vs Me 8.5 (IQR 5.9-12.6) p < 0.0001). NRF2 mRNA level was positively correlated with expression of all investigated NRF2-target genes in both groups (0.37 > R < 0.76, all p values < 0.0001). The multivariate linear regression adjusting for global methylation showed that As(III) level was significantly associated with expression of TXNRD1, GSTP1, HMOX1, and PRDX1. The results of this study indicate that arsenic occupational exposure is positively associated with global DNA methylation. The findings provide evidence for rather inactivation of NRF2-KEAP1 pathway in response to chronic arsenic exposure.

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Nrf2 activation ameliorates cytotoxic effects of arsenic trioxide in acute promyelocytic leukemia cells through increased glutathione levels and arsenic efflux from cells

Cited by 21 publications

References 42 publications

The short isoform of PML‐RARα activates the NRF2/HO‐1 pathway through a direct interaction with NRF2

The short isoform of PML‐RARα activates the NRF2/HO‐1 pathway through a direct interaction with NRF2

Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols

Effect of arsenic exposure on Nrf2-Keap1 pathway and epigenetic modification

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