Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation

Tsuchida, Kouhei; Tsujita, Teppei; Hayashi, Makiko; Ojima, Asaka; Keleku-Lukwete, Nadine; Katsuoka, Fumiki; Otsuki, Akihito; Kikuchi, Haruhisa; Oshima, Yoshiteru; Suzuki, Mikiko; Yamamoto, Masayuki

doi:10.1016/j.freeradbiomed.2016.12.041

Cited by 133 publications

(96 citation statements)

References 56 publications

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“…For instance, promising results with brusatol were recently discouraged by the finding that this drug exerts a general and unspecific inhibition of protein synthesis, resulting in the drop of NRF2 levels, but also of many other proteins with rapid turnover (Harder et al, 2017). Similarly, the antiprotozoal agent halofuginone, used in veterinary practice, enhances the chemosensitivity of cancer cells by suppressing NRF2 accumulation, but this effect appears to be indirect by inhibiting prolyl-transfer RNA synthesis that is strongly required for ribosomal translation of NRF2 as well as many other proline-containing proteins (Tsuchida et al, 2017).…”

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…Though HT-100, an oral analog of halofuginone, was studied in a phase 2 clinical trial for bladder cancer treatment, development of the compound was discontinued. Quite recently, halofuginone was found to inhibit NRF2 (87). …”

Section: Nrf2 Inhibitorsmentioning

confidence: 99%

The KEAP1–NRF2 System in Cancer

2017

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Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2. Unregulated NRF2 confers on cancer cells high-level resistance to anticancer drugs and reactive oxygen species (ROS) and directs cancer cells toward metabolic reprogramming. Therefore, NRF2 has been studied as a therapeutic target molecule in cancer. Two strategies have been used to target NRF2 via therapeutic drugs: inhibition of NRF2 and induction of NRF2. NRF2 inhibitors may be effective against NRF2-addicted cancer cells in which NRF2 is aberrantly activated. These inhibitors have not yet been established as NRF2-targeted anticancer drugs for the treatment of human cancers. Diagnosis of NRF2 activation could facilitate the use of NRF2 inhibitors for the treatment of patients with NRF2-addicted cancers. Conversely, NRF2 inducers have been used or are being developed for non-cancer diseases. In addition, NRF2 inducers may be useful for cancer chemotherapy in combination with conventional anticancer agents or even NRF2 inhibitors.

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“…This compound was discovered using A549 lung cancer cells, which harbor constitutively active Nrf2 due to an inactivating mutation in KEAP1. Halofuginone selectively targeted Nrf2-addicted cancer cells, sensitizing them to chemotherapy [93]. Combined treatment of halofuginone and cisplatin also decreased tumor growth in a mouse xenograft model.…”

Section: Targeting Nrf2 Signalingmentioning

confidence: 99%

Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia

2017

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The importance of the tumor microenvironment for cancer progression and therapeutic resistance is an emerging focus of cancer biology. Hypoxia, or low oxygen, is a hallmark of solid tumors that promotes metastasis and represents a significant obstacle to successful cancer therapy. In response to hypoxia, cancer cells activate a transcriptional program that allows them to survive and thrive in this harsh microenvironment. Hypoxia-inducible factor 1 (HIF-1) is considered the main effector of the cellular response to hypoxia, stimulating the transcription of genes involved in promoting angiogenesis and altering cellular metabolism. However, growing evidence suggests that the cellular response to hypoxia is much more complex, involving coordinated signaling through stress response pathways. One key signaling molecule that is activated in response to hypoxia is nuclear factor, erythroid 2 like-2 (Nrf2). Nrf2 is a transcription factor that controls the expression of antioxidant-response genes, allowing the cell to regulate reactive oxygen species. Nrf2 is also activated in various cancer types due to genetic and epigenetic alterations, and is associated with poor survival and resistance to therapy. Emerging evidence suggests that coordinated signaling through Nrf2 and HIF-1 is critical for tumor survival and progression. In this review, we discuss the distinct and overlapping roles of HIF-1 and Nrf2 in the cellular response to hypoxia, with a focus on how targeting Nrf2 could provide novel chemotherapeutic modalities for treating solid tumors.

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Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation

Cited by 133 publications

References 56 publications

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

The KEAP1–NRF2 System in Cancer

Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia

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