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Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity
Harit Panda1, Mikiko Suzuki2, Mitsuru Naito3
1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
Abstract:
The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings.
Insights
Halofuginone (HF) effectively inhibits cancer cell growth but causes severe immune suppression. Encapsulating HF into micelles (HFm) reduces toxicity while preserving anti-cancer effects, offering a promising therapeutic strategy for Nrf2-activated tumors.
Area of Science:
- Biochemistry
- Oncology
- Nanomedicine
Background:
- The Keap1-Nrf2 pathway regulates cellular stress responses and is constitutively activated in many cancers.
- Nrf2 hyperactivation promotes cancer cell proliferation, metabolic reprogramming, and resistance to radio/chemotherapy.
- Targeting Nrf2 is a key strategy to overcome treatment resistance in Nrf2-activated tumors.
Purpose of the Study:
- To evaluate Halofuginone (HF) as a therapeutic agent against Nrf2-activated cancers.
- To address the dose-dependent hematopoietic and immune cell suppression caused by HF.
- To develop a nanomedicine approach for HF delivery to mitigate toxicity.
Main Methods:
- Preclinical characterization of Halofuginone (HF) in cancer cells.
- Development and evaluation of HF-loaded polymeric micelles (HFm).
- Liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze HF release kinetics.
Main Results:
- HF demonstrated significant cancer cell viability reduction but induced severe systemic toxicity.
- HFm formulation largely alleviated HF-induced toxicity while retaining anti-tumor efficacy.
- Slow and sustained release of HF from HFm core was confirmed by LC-MS/MS, correlating with reduced adverse effects.
Conclusions:
- HFm represents a promising nanomedicine approach to counteract Nrf2-activated cancers.
- The developed HFm formulation mitigates HF's systemic toxicity, enhancing its therapeutic potential.
- This strategy supports the clinical application of HF for treating resistant cancers.
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