Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC’s antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency in vitro. PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC in vitro, the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis.

Parthenolide Induces ROS-Mediated Apoptosis in Lymphoid Malignancies

“…A more recent study in hepatocellular carcinoma cells showed that parthenolide depleted intracellular thiols (e.g., GSH) by increasing cytosolic and mitochondrial thiol oxidation, leading to early mitochondrial dysfunction and oxidative stress. This was accompanied by an increase in lipid peroxidation leading to ferroptosis, an irreversible mechanism of cell death [10].…”

“…Parthenolide is a naturally occurring sesquiterpene lactone isolated from feverfew (Tanacetum parthenium), a traditional medicinal plant that has been conventionally used in the treatment of fever, migraines, and arthritis. Parthenolide has also been highly studied for its anticancer activities in multiple cancer types, including hepatocellular carcinoma, breast cancer, and hematological malignancies [10][11][12][13][14][15][16], among others. The variety of biological activities associated with parthenolide are mainly related to its chemical structure, which includes an α-methylene-γ-lactone ring and epoxide group capable of interacting with the nucleophilic sites of various proteins, ultimately interfering with different signaling pathways (Figure 1) [17].…”

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

“…Pien-Tze-Huang, a Chinese patent medicine approved by China Food and Drug Administration, may effectively improve the microenvironment of LF and inhibit the occurrence of HCC through triggering ferroptosis of tumor cells via suppressing the SLC7A11-GSH-GPX4 axis [228]. Moreover, rhamnazin [229], polyphyllin VI [230], corosolic acid [231], solasonine [232], parthenolide [233], cryptotanshinone [234], and heteronemin [235] could trigger ferroptosis in HCC cells through down-regulating GPX4 expression. Among them, parthenolide, cryptotanshinone, corosolic acid, and solasonine could also inhibit the synthesis of GSH by rapid thiol oxidation [233] and reducing the expression of SCL7A11 [234] and glutathione synthetase (GSS) [231,232], respectively.…”

“…Moreover, rhamnazin [229], polyphyllin VI [230], corosolic acid [231], solasonine [232], parthenolide [233], cryptotanshinone [234], and heteronemin [235] could trigger ferroptosis in HCC cells through down-regulating GPX4 expression. Among them, parthenolide, cryptotanshinone, corosolic acid, and solasonine could also inhibit the synthesis of GSH by rapid thiol oxidation [233] and reducing the expression of SCL7A11 [234] and glutathione synthetase (GSS) [231,232], respectively. Interestingly, aspirin, a derivative of salicylic acid, could trigger ferroptosis by restricting NF-κB-activated SLC7A11 transcription, thereby inhibiting the growth of HCC [236].…”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…Consistently, in vivo studies have confirmed that corosolic acid inhibits tumor growth by promoting HERPUD1‐mediated ferroptosis (Y. Peng, Li, et al, 2022). Strikingly, parthenolide decreased the levels of intracellular reduced GSH by oxidizing the sulfhydryl group of GSH, thereby enhancing the sensitivity of HCC cells to ferroptosis (LoBianco et al, 2022). These data suggest that the SLC7A11/GSH/GPX4 system is a key target by which terpenoids inhibit cancer progression.…”