Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity

Panda, Harit; Suzuki, Mikiko; Naito, Mitsuru; Saito, Ryosuke; Wen, Huaichun; Baird, Liam; Uruno, Akira; Miyata, Kanjiro; Yamamoto, Masayuki

doi:10.1016/j.freeradbiomed.2022.05.017

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…Halofuginone suppresses NRF2 protein accumulation by inhibition of prolyl-tRNA synthetase. Recently, we developed novel compound “halofuginone-micelle” which attacks NRF2-activated cancers with less adverse effect ( Panda et al, 2022 ). Another promising approach is to isolate synthetic lethal drugs including mitomycin C and the geldanamycin-derived HSP90 inhibitor ( Baird and Yamamoto, 2021 ; Baird et al, 2020 ) ( Fig.…”

Section: Therapeutic Strategies To Control Nrf2-overactivated Cancersmentioning

confidence: 99%

Molecular Basis of the KEAP1-NRF2 Signaling Pathway

Suzuki

Takahashi

Yamamoto

2023

Molecules and Cells

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Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.

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Section: Therapeutic Strategies To Control Nrf2-overactivated Cancersmentioning

confidence: 99%

Molecular Basis of the KEAP1-NRF2 Signaling Pathway

Suzuki

Takahashi

Yamamoto

2023

Molecules and Cells

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“…In addition, Halofuginone (HF) is a promising Nrf2 inhibitor ( 212 ). HF significantly reduced the viability of cancer cells, caused severe hematopoietic and immune cell suppression in a dose-dependent manner ( 213 ). By taking a nanomedicine approach and encapsulating HF into polymer micelles (HF micelles; HFm), the systemic toxicity exhibited by free HF can be mitigated while maintaining antitumor properties.…”

Section: Agents Targeting Nrf2’s Therapeutic Role In Human Cancersmentioning

confidence: 99%

Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers

Lin,

Wu,

et al. 2023

Front. Oncol.

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Cancer is a borderless global health challenge that continues to threaten human health. Studies have found that oxidative stress (OS) is often associated with the etiology of many diseases, especially the aging process and cancer. Involved in the OS reaction as a key transcription factor, Nrf2 is a pivotal regulator of cellular redox state and detoxification. Nrf2 can prevent oxidative damage by regulating gene expression with antioxidant response elements (ARE) to promote the antioxidant response process. OS is generated with an imbalance in the redox state and promotes the accumulation of mutations and genome instability, thus associated with the establishment and development of different cancers. Nrf2 activation regulates a plethora of processes inducing cellular proliferation, differentiation and death, and is strongly associated with OS-mediated cancer. What’s more, Nrf2 activation is also involved in anti-inflammatory effects and metabolic disorders, neurodegenerative diseases, and multidrug resistance. Nrf2 is highly expressed in multiple human body parts of digestive system, respiratory system, reproductive system and nervous system. In oncology research, Nrf2 has emerged as a promising therapeutic target. Therefore, certain natural compounds and drugs can exert anti-cancer effects through the Nrf2 signaling pathway, and blocking the Nrf2 signaling pathway can reduce some types of tumor recurrence rates and increase sensitivity to chemotherapy. However, Nrf2’s dual role and controversial impact in cancer are inevitable consideration factors when treating Nrf2 as a therapeutic target. In this review, we summarized the current state of biological characteristics of Nrf2 and its dual role and development mechanism in different tumor cells, discussed Keap1/Nrf2/ARE signaling pathway and its downstream genes, elaborated the expression of related signaling pathways such as AMPK/mTOR and NF-κB. Besides, the main mechanism of Nrf2 as a cancer therapeutic target and the therapeutic strategies using Nrf2 inhibitors or activators, as well as the possible positive and negative effects of Nrf2 activation were also reviewed. It can be concluded that Nrf2 is related to OS and serves as an important factor in cancer formation and development, thus provides a basis for targeted therapy in human cancers.

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“…Since xCT overexpression may be due to the increased activity of Nrf2, the compounds targeting this transcription factor have been proposed to treat cancer and/or to counteract the onset of chemoresistance. In this regard, natural compounds such as brusatol, halofuginone luteolin, chrysin and emetine showed anticancer properties (Table 1) [Xiang Y, Ye W et al 2018;Panda H, Suzuki M et al 2022] and a chemosensitizer action [Panieri E, Saso L 2019].…”

Section: Gsh Precursor Amino Acid Uptake Inhibitorsmentioning

confidence: 99%

Glutathione in cancer progression and chemoresistance: an update

Valenti

Tasso

Traverso

et al. 2023

Redox Experimental Medicine

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Glutathione is one of the most important components of the cellular antioxidant system and it is able to exert several pleiotropic functions influencing cell growth, proliferation, adaptation and death. It has been demonstrated that changes in glutathione levels underlie the pathogenesis of many human diseases, including cancer. In detail, although on one hand glutathione homeostasis plays a protective role from the onset of cancer, on the other, it is involved in cancer progression and in therapy resistance. Objective: In this review, after a brief report on the physiological role of glutathione, we have focused the attention on its role in cancer and refractoriness to anticancer therapy giving an update on the preclinical and clinical studies relied on the compounds targeting glutathione system. Conclusions and significance: Based on these considerations, a deeper knowledge of glutathione-dependent network can be crucial to identify new strategies for preventing and/or curing cancer.

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Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity

Cited by 9 publications

References 40 publications

Molecular Basis of the KEAP1-NRF2 Signaling Pathway

Molecular Basis of the KEAP1-NRF2 Signaling Pathway

Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers

Glutathione in cancer progression and chemoresistance: an update

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