Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo

Chian, Song; Thapa, Ruby; Chi, Zhexu; Wang, Xiu Jun; Tang, Xiuwen

doi:10.1016/j.bbrc.2014.04.039

Cited by 121 publications

(71 citation statements)

References 26 publications

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“…Gefitinib was found less effective than luteolin in prostate cancer (41,42), while lapatinib and luteolin were similarly effective against breast cancer (43). Combining luteolin with cisplatin or AG1478 unveiled a synergism in SCC-25 cells, similar to previous reports in liver, colorectal, gastric, pancreatic, and lung cancer (44)(45)(46), although not the case in breast and prostate cancer cells (41,43). Given the concern of broad toxicity of cisplatin and the adverse effects of tyrosine kinase inhibitors, such as gefitinib and lapatinib, luteolin appears to be a promising candidate for future clinical application, against OSCC.…”

Section: Discussionsupporting

confidence: 81%

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

Tjioe

Oliveira

Gavard

2016

Nutrition and Cancer

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Oral squamous cell carcinoma (OSCC) exhibited high chemoresistance to current treatments. Here we aimed at identifying and repositioning approved drugs that could be selectively toxic toward OSCC cells. Through a cell-based drug screening of 1,280 chemical molecules, we selected compounds lethal to oral cancer SCC-25 cells, while sparing normal keratinocyte HaCaT cells. Within the chemical library, the natural flavonoid luteolin was identified as a potent cytotoxic agent against oral cancer cells in vitro, along with metixene hydrochloride and nitazoxanide. Of note, they exhibit low toxicity and high efficiency compared to the standard-of-care, such as cisplatin and the epidermal growth factor receptor inhibitor tyrphostin. From a molecular standpoint, luteolin causes phosphorylation of ataxia telangiectasia mutated (ATM) and H2AX in a DNA repair pathway and can be efficiently combined with a checkpoint kinase (CHK) pharmacological inhibitor. Thus, luteolin emerges as a potent cytotoxic and/or adjuvant therapy in oral cancer, as it is a natural compound presenting better effects in vitro compared to conventional chemotherapeutic agents. Future in vivo exploration is next required to provide the proof-of-concept that luteolin could be an efficient anticancer molecule.

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Section: Discussionsupporting

confidence: 81%

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

Tjioe

Oliveira

Gavard

2016

Nutrition and Cancer

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“…An increasing number of studies have been focusing on Chinese herb extracts, with certain compounds recently reported as molecular targeted anti-cancer drugs, such as luteolin, a novel inhibitor of RSK. Luteolin has been the focus of clinical-translational interest in anticancer treatment (31)(32)(33). In the present study, the effects of pharmacological inhibition of the RSK1 inhibitor, luteolin, on leukemic cell lines were investigated.…”

Section: A B C D Ementioning

confidence: 98%

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Deng

Jiang

et al. 2017

Oncology Letters

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Abstract. Ribosomal S6 kinases (RSKs) are directly regulated by extracellular signal-regulated kinase (ERK) signaling and are implicated in cell growth, survival, motility and senescence. The present study observed that RSK1 was overexpressed in primary untreated leukemia patient bone marrow samples compared with the expression at the complete remission stage, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a high RSK1 expression (relative expression ≥10) was associated with a significantly shorter overall survival (P=0.038) compared with that in patients with low RSK1 expression (relative expression <10). The current study also investigated the effect of luteolin, a novel p90 ribosomal S6 kinase (RSK) inhibitor extracted from Reseda odorata L., which shows strong biochemical functions including anti-allergy, anti-inflammation and anti-cancer functions, in MOLM-13 and Kasumi-1 leukemic cells. The cell viability, apoptosis and migration ability analysis were assessed by performing a cell counting kit-8 assay, Annexin V-FITC/PI double staining and migration filter assay, respectively. The results indicated that luteolin inhibited the growth of the leukemic cell lines through induction of apoptosis, while the migration ability was also suppressed. Overexpression of RSK1 by plasmid transfection was found to decrease the luteolin-induced apoptosis and migration capabilities. By contrast, knockdown of the RSK1 expression by small interfering RNA appeared to induce the same effect as luteolin on MOLM-13 and Kasumi-1 leukemic cells. In conclusion, these results suggest that luteolin inhibits leukemic cell proliferation and induces apoptosis by inhibition of the RSK1 pathways. IntroductionRibosomal S6 kinases (RSKs) are a family of serine/threonine protein kinases that are directly regulated by extracellular signal-regulated kinase (ERK) signaling. RSK1, a member of the RSK family, was initially identified as an X-linked gene in patients with mental retardation (1-3). Typically, RSK is expressed in the cerebellum during embryogenesis and silenced postnatally. Aberrant RSK signaling is integral for various types of cancer, including breast, colon and renal cancer, as well as melanoma. Li et al (4) observed that the p90 RSK2-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells. Degen et al (5) also demonstrated this phenomenon, and further observed that overexpression of RSK3 and RSK1 supports cellular proliferation under the PI3K signaling pathway blockade. This occurs through the inhibition of apoptosis and regulation of cellular translation in squamous carcinoma cell through phosphorylation of RSK and eukaryotic translation initiation factor 4B. It is thus reported that RSK1 serves a role in squamous carcinoma cell growth and proliferation. In addition, Cohen et al (6) observed that RSK1 overexpression is associated with sunitinib resistance in renal cell carcinoma cell lines. Elf et al (7) also reported that, altho...

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“…Brusatol inhibits in vivo tumor growth while enhancing chemosensitivity, indicating its beneficial effect as a combinatorial therapy. Luteolin, a flavonoid that also exists in plants and vegetables, blocks subcutaneous lung tumor cell growth and proliferation in mice while increasing cytotoxicity of cisplatin treatment [126, 127]. Ascorbic acid and all-trans -retinoic acid (ATRA), other natural compounds, suppress NRF2 activation by interfering with nuclear localization of Nrf2 or its binding to ARE [128, 129].…”

Section: Modulation Of Nrf2 Signaling: Nrf2 Inhibitorsmentioning

confidence: 99%

Dual roles of NRF2 in tumor prevention and progression: Possible implications in cancer treatment

Moon

Giaccia

2015

Free Radical Biology and Medicine

142

112

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The Cap’N’Collar (CNC) family serves as cellular sensors of oxidative and electrophilic stresses and shares structural similarities including basic leucine zipper (bZIP) and CNC domains,. They form heterodimers with small MAF proteins to regulate antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. Among the CNC family members, NRF2 is required for systemic protection against redox-mediated injury and carcinogenesis. On the other hand, NRF2 is activated by oncogenic pathways, metabolism, and hypoxia. Constitutive NRF2 activation is observed in a variety of human cancers and it is highly correlated with tumor progression and aggressiveness. In this review, we will discuss how NRF2 plays dual roles in cancer prevention and progression depending on the cellular context and environment. Therefore, a better understanding of NRF2 will be necessary to exploit this complex network of balancing antioxidant pathways to inhibit tumor progression.

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Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo

Cited by 121 publications

References 26 publications

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Dual roles of NRF2 in tumor prevention and progression: Possible implications in cancer treatment

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