Suppression of NRF2–ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells

Peng, Hui; Wang, Huihui; Xue, Peng; Hou, Yongyong; Dong, Jian; Zhou, Tong; Qu, Weidong; Peng, Shuangqing; Li, Jin; Carmichael, Paul L.; Nelson, B.W.; Clewell, Rebecca A.; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

doi:10.1016/j.taap.2015.12.008

Cited by 36 publications

(26 citation statements)

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“…Therefore, compound 4f inhibits AML cell growth, which is associated with Nrf2 suppression. Consistent with our results, a recent study showed that silencing of Nrf2 in THP-1 cells sensitized the cells to cytotoxicity by multiple agents [29]. Additionally, Nrf2 activation was found to protect AML cells against As 2 O 3 or bortezomib-induced apoptosis [29, 30].…”

Section: Discussionsupporting

confidence: 91%

“…Consistent with our results, a recent study showed that silencing of Nrf2 in THP-1 cells sensitized the cells to cytotoxicity by multiple agents [29]. Additionally, Nrf2 activation was found to protect AML cells against As 2 O 3 or bortezomib-induced apoptosis [29, 30]. The evidence has implied more effective growth inhibition of cancer cells when combining the compounds with Nrf2 inhibitors, such as 4f.…”

Section: Discussionsupporting

confidence: 89%

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Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells

Zhang

et al. 2016

Oncotarget

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Nuclear factor-erythroid 2-related factor 2 (Nrf2) is persistently activated in many human tumors including acute myeloid leukemia (AML). Therefore, inhibition of Nrf2 activity may be a promising target in leukemia therapy. Here, we used an antioxidant response element-luciferase reporter system to identify a novel pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole-5-carboxamide (4f), that inhibited Nrf2 activity. 4f had a profound growth-inhibitory effect on three AML cell lines, THP-1, HL-60 and U937, and a similar anti-growth effect in a chick embryo model. Moreover, flow cytometry of AML cells revealed increased apoptosis with 4f (10 μM) treatment for 48 h. The protein levels of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase were enhanced in all three AML cell types. Furthermore, Nrf2 protein level was downregulated by 4f. Upregulation of Nrf2 by tert-butylhydroquinone (tBHQ) or Nrf2 overexpression could ameliorate 4f-induced growth inhibition and apoptosis. Treatment with 4f reduced both B-cell lymphoma-2 (Bcl-2) expression and Bcl-2/Bcl-2–associated X protein (Bax) ratio, which indicated that 4f induced apoptosis, at least in part, via mitochondrial-dependent signaling. Therefore, as an Nrf2 inhibitor, the pyrazolyl hydroxamic acid derivative 4f may be a promising agent in AML therapy.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells

Zhang

et al. 2016

Oncotarget

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“…Induction failure and a high incidence of relapse due to drug resistance are the principal problems surrounding AML treatment (2,18). The use of novel drugs is one approach for treating patients who are resistant to standard therapies (19).…”

Section: Discussionmentioning

confidence: 99%

“…The principal therapeutic strategies for patients with AML are aggressive chemotherapeutic regimens and hematopoietic stem cell transplantation (HSCT) (1)(2)(3). However, AML consists of 8 subtypes, including M 0 (minimally differentiated AML), M 1 (AML without maturation), M 2 (AML with maturation), M 3 (acute promyelocytic leukemia), M 4 (acute myelomonocytic leukemia), M 5 [acute monocytic leukemia (AMoL)], M 6 (erythroleukemia) and M 7 (acute megakaryoblastic leukemia).…”

Section: Introductionmentioning

confidence: 99%

“…There are various chemotherapy regimens used to treat patients with AMoL including: i) Homoharringtonine, cytarabine and etoposide; ii) daunorubicin, Ara-c and teniposide; and iii) mitoxantrone, Ara-c and teniposide (7). However, AMoL is insensitive to a number of chemotherapy regimens, thus patients with AMoL exhibit a low remission rate and decreased survival time (2,6,7). Therefore, novel effective drugs are required.…”

Section: Introductionmentioning

confidence: 99%

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Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells

Cao

Wang

et al. 2017

Oncol Lett

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Abstract. Dihydroartemisinin (DHA) is a derivative of artemisinin. The present study aimed to investigate whether DHA induces apoptosis in the THP-1 human acute monocytic leukemia cell line (AMoL), and to identify the relative molecular mechanisms. The results of the present study demonstrated that the viability of THP-1 cells were inhibited by DHA in a dose-and time-dependent manner, which was accompanied by morphological characteristics associated with apoptosis. After 24 h of 200 µM DHA treatment, the proportion of apoptotic cells was significantly increased compared with the untreated controls (P<0.01). In addition, DHA downregulated the levels of B-cell lymphoma (Bcl)-2, protein kinase B (Akt)1, Akt2 and Akt3 gene expression, and increased the expression of the Bcl-2-associated X protein apoptosis regulator. The protein expression of phospho-Akt and phospho-extracellular signal-regulated kinase (ERK) was also decreased, and the protein expression level of cleaved caspase-3 was increased following treatment with DHA. Therefore, DHA may induce apoptosis in the AMoL THP-1 cell line via currently unknown underlying molecular mechanisms, including the downregulation of ERK and Akt, and the activation of caspase-3.

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