Ethanol extract of Eclipta prostrata induces multiple myeloma ferroptosis via Keap1/Nrf2/HO-1 axis.

BACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy with limited therapeutic efficacy. Eclipta prostrata is a traditional Chinese medicinal plant reported to possess antitumor properties. However, the effects of E. prostrata in MM have not been explored. PURPOSE: The aim of this study was to define the mechanism of the ethanol extract of E. prostrata (EEEP) in treating MM and identify its major components. METHODS: The pro-ferroptotic effects of EEEP on cell death, cell proliferation, iron accumulation, lipid peroxidation, and mitochondrial morphology were determined in RPMI-8226 and U266 cells. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and 4-hydroxynonenal (4HNE) were detected using western blotting during EEEP-mediated ferroptosis regulation. The RPMI-8226 and U266 xenograft mouse models were used to explore the in vivo anticancer effects of EEEP. Finally, high performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry system (UPLC-Q/TOF-MS) were used to identify the major constituents of EEEP. RESULTS: EEEP inhibited MM cell growth and induced cell death in vitro and in vivo. By promoting malondialdehyde and Fe2+ accumulation, lipid peroxidation, and GSH suppression, EEEP triggers ferroptosis in MM. Mechanistically, EEEP regulates the Keap1/Nrf2/HO-1 axis and stimulates ferroptosis. EEEP-induced lipid peroxidation and malondialdehyde accumulation were blocked by the Nrf2 activator NK-252. In addition, HPLC and UPLC-Q/TOF-MS analysis elucidated the main components of EEEP, including demethylwedelolactone, wedelolactone, chlorogenic acid and apigenin, which may play important roles in the anti-tumor function of EEEP. CONCLUSION: In summary, EEEP exerts its anti-MM function by inducing MM cell death and inhibiting tumor growth in mice. We also showed that EEEP can induce lipid peroxidation and accumulation of ferrous irons in MM cells both in vivo and in vitro, leading to ferroptosis. In addition, this anti-tumor function may be achieved by the EEEP activation of Keap1/Nrf2/HO-1 axis. This is the first study to reveal that EEEP exerts anti-MM activity through the Keap1/Nrf2/HO-1-dependent ferroptosis regulatory axis, making it a promising candidate for MM treatment.

Harnessing Nanotechnology: Emerging Strategies for Multiple Myeloma Therapy.

Advances in nanotechnology have provided novel avenues for the diagnosis and treatment of multiple myeloma (MM), a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. This review elucidates the potential of nanotechnology to revolutionize myeloma therapy, focusing on nanoparticle-based drug delivery systems, nanoscale imaging techniques, and nano-immunotherapy. Nanoparticle-based drug delivery systems offer enhanced drug targeting, reduced systemic toxicity, and improved therapeutic efficacy. We discuss the latest developments in nanocarriers, such as liposomes, polymeric nanoparticles, and inorganic nanoparticles, used for the delivery of chemotherapeutic agents, siRNA, and miRNA in MM treatment. We delve into nanoscale imaging techniques which provide spatial multi-omic data, offering a holistic view of the tumor microenvironment. This spatial resolution can help decipher the complex interplay between cancer cells and their surrounding environment, facilitating the development of highly targeted therapies. Lastly, we explore the burgeoning field of nano-immunotherapy, which employs nanoparticles to modulate the immune system for myeloma treatment. Specifically, we consider how nanoparticles can be used to deliver tumor antigens to antigen-presenting cells, thus enhancing the body's immune response against myeloma cells. In conclusion, nanotechnology holds great promise for improving the prognosis and quality of life of MM patients. However, several challenges remain, including the need for further preclinical and clinical trials to assess the safety and efficacy of these emerging strategies. Future research should also focus on developing personalized nanomedicine approaches, which could tailor treatments to individual patients based on their genetic and molecular profiles.