Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis

By J. Roh, Eun Hye Kim, Hyejin Jang, Daiha Shin. Redox Biology, 2016

599 citations recorded by the source corpus.

Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin-resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2–antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2–ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC. Condensed abstract Our results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron-dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2–antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2–ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells.

Subfields: Immunology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/6914466a02c5b6d83972aed9aa010684f06505d5

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Citations in the corpus

The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “The activation of Nrf2-antioxidant response element (ARE) pathway can decrease artesunate sensitivity and increase the ferroptosis resistance in cisplatin-resistant HNC cells.(94) The Nrf2-ARE pathway also contributes to the resistance of HNC cells by inhibiting GPX4.”
NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis (2019, background): “Indeed, treatment with trigonelline has been shown to enhance sorafenib-induced hepatocellular carcinoma cell death [57] and artesunate-induced ferroptosis in head and neck cancer cell lines [58].”
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs.”
Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “In addition, trigonelline is a plant alkaloid that significantly reduces GSH levels, thus induces ferroptosis in head and neck cancer cells [276].”
The Roles of NRF2 in Modulating Cellular Iron Homeostasis (2017, background): “NRF2 activation also contributes to ferroptosis resistance of head and neck cancer cells; importantly, in vivo inhibition of the NRF2 pathway sensitized ferroptosis-resistant head and neck cancers to 50 mg/kg of artesunate, a ferroptosis inducer (130).”