👤 G Baird

Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cancer development, progression, and resistance to therapy. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-antioxidant response element (ARE) signaling pathway is central to maintaining redox balance by regulating the expression of antioxidant and detoxification genes. Under physiological conditions, this pathway protects cells from oxidative damage, however, sustained activation of NRF2 in cancer, often due to mutations in KEAP1, supports tumor cell survival, drug resistance, and metabolic reprogramming. Recent studies demonstrate that NRF2 enhances glutathione (GSH) synthesis, induces detoxifying enzymes, and upregulates drug efflux transporters, collectively contributing to resistance against chemotherapy and targeted therapies. The inhibition of NRF2 using small molecules or dietary phytochemicals has shown promise in restoring drug sensitivity in preclinical cancer models. This review highlights the dual role of NRF2 in redox regulation and cancer therapy, emphasizing its potential as a therapeutic target. While targeting NRF2 offers a novel approach to overcoming treatment resistance, further research is needed to enhance specificity and facilitate clinical translation. Show less

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. Show less

Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca 2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca 2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression. Show less