Dimethyl fumarate and vitamin D derivatives cooperatively enhance VDR and Nrf2 signaling in differentiating AML cells in vitro and inhibit leukemia progression in a xenograft mouse model

Nachliely, Matan; Trachtenberg, Aviram; Khalfin, Boris; Nalbandyan, Karen; Cohen-Lahav, Merav; Yasuda, Kaori; Sakaki, Toshiyuki; Kutner, Andrzej; Danilenko, Michael

doi:10.1016/j.jsbmb.2018.11.017

Cited by 27 publications

(38 citation statements)

References 39 publications

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“…Nrf2 signaling-based anticancer therapeutic studies have been extensively carried out in multiple cancers, including acute myeloid leukemia, gallbladder cancer, renal carcinoma, pancreatic cancer, melanoma, hepatocellular carcinoma, lung cancer, colon cancer, ovarian cancer, breast cancer, esophageal cancer, and glioblastoma (Table 1). i) In acute myeloid leukemia, studies found that Nrf2 activators [dimethyl fumarate (DMF), tert-butylhydroquinone, or carnosic acid] and vitamin D derivatives can cooperatively induce acute myeloid leukemia cell differentiation to inhibit leukemia progression in a xenograft mouse model via activating the Nrf2/ARE signaling pathway (Nachliely et al, 2019). Novel pyrazolyl hydroxamic acid derivative (4f) can inhibit Nrf2 activity to induce apoptosis of human acute myeloid leukemia cells (Zhang et al, 2017).…”

Section: Therapeutic Status Targeting Nrf2 Signaling Pathways In Cancersmentioning

confidence: 99%

Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas

Zhan

Zhou

2021

Front. Pharmacol.

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Oxidative stress and oxidative damage are the common pathophysiological characteristics in pituitary adenomas (PAs), which have been confirmed with many omics studies in PA tissues and cell/animal experimental studies. Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), the core of oxidative stress response, is an oxidative stress sensor. Nrf2 is synthesized and regulated by multiple factors, including Keap1, ERK1/2, ERK5, JNK1/2, p38 MAPK, PKC, PI3K/AKT, and ER stress, in the cytoplasm. Under the oxidative stress status, Nrf2 quickly translocates from cytoplasm into the nucleus and binds to antioxidant response element /electrophile responsive element to initiate the expressions of antioxidant genes, phases I and II metabolizing enzymes, phase III detoxifying genes, chaperone/stress response genes, and ubiquitination/proteasomal degradation proteins. Many Nrf2 or Keap1 inhibitors have been reported as potential anticancer agents for different cancers. However, Nrf2 inhibitors have not been studied as potential anticancer agents for PAs. We recommend the emphasis on in-depth studies of Nrf2 signaling and potential therapeutic agents targeting Nrf2 signaling pathways as new therapeutic strategies for PAs. Also, the use of Nrf2 inhibitors targeting Nrf2 signaling in combination with ERK inhibitors plus p38 activators or JNK activators targeting MAPK signaling pathways, or drugs targeting mitochondrial dysfunction pathway might produce better anti-tumor effects on PAs. This perspective article reviews the advances in oxidative stress and Nrf2-mediated oxidative stress response signaling pathways in pituitary tumorigenesis, and the potential of targeting Nrf2 signaling pathways as a new therapeutic strategy for PAs.

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Section: Therapeutic Status Targeting Nrf2 Signaling Pathways In Cancersmentioning

confidence: 99%

Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas

Zhan

Zhou

2021

Front. Pharmacol.

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“…The combination of calcitriol, a synthetic form of vitamin D3, with azacytidine, the main demethylating agent for the treatment of myelodysplastic syndrome, showed synergistic inhibition on the proliferation of HL-60 and MOLM13 cells [ 82 ]. In addition, combining 1,25-dihydroxyvitamin D3 or its analogs with dimethyl fumarate, a nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf2) activator and clinically approved agent for multiple sclerosis and psoriasis, induced strong synergistic pro-differentiating effects in HL-60 cells through cooperatively upregulating VDR and Nrf2 [ 86 ]. Another study combined calcitriol with glycogen synthase kinase 3 (GSK3) inhibitors and showed that HL-60 and OCI-AML3 cells were able to undergo further differentiation upon treatment.…”

Section: Potential Roles Of Nrs In Acute Myeloid Leukemiamentioning

confidence: 99%

Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia

Pan¹,

Chen²

2020

Cells

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The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs.

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“…Preclinical studies in tumor models have also shown significant antitumor activity of DMF, which has been linked to its ability to activate Nrf2 and inhibit the NF-κB pathways [214,215] . Promising results have been observed with DMF in several types of cancer models such as glioblastoma, breast cancer, KRAS mutated cancers and myelogenous leukemia [216][217][218][219] . However, to our knowledge, the efficacy of DMF in prostate cancer patients, and especially, its ability to suppress CRPC progression has not been investigated so far.…”

Section: Repurposed Agentsmentioning

confidence: 99%

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

Mondal¹,

Narwani²,

Notta³

et al. 2020

CDR

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Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

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Dimethyl fumarate and vitamin D derivatives cooperatively enhance VDR and Nrf2 signaling in differentiating AML cells in vitro and inhibit leukemia progression in a xenograft mouse model

Cited by 27 publications

References 39 publications

Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas

Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas

Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

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