image: AZD1775 plays a role in the regulation of ferroptosis by dually targeting the cystine uptake and the WEE1-SETDB1 axis, while the activation of the p53-SLC7A11 cascade by Act. D augments AZD1775-induced ferroptosis to suppress cancers harboring wild-type p53.
Credit: ©Science China Press
Ferroptosis is a unique form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a crucial role in cancer treatment by eliminating tumor cells. However, cancer cells often develop resistance to ferroptosis by activating antioxidant defenses, making it challenging to achieve effective therapeutic outcomes through single-agent treatments.
Recent research conducted by a team led by Dr. Xiang Zhou at Fudan University reveals that the combination of the WEE1 inhibitor AZD1775 with the nucleolar stress inducer actinomycin D can effectively induce ferroptosis in lung cancer cells, leading to substantial suppression of tumor growth. This study, published in Science China Life Sciences, demonstrates the potential of the combination therapy in overcoming ferroptosis resistance in cancer cells.
The study highlights that AZD1775 inhibits the activity of the system xc– transporter, blocking the uptake of cystine, which is essential for glutathione synthesis and antioxidant defense in cancer cells. This inhibition triggers lipid peroxidation, leading to ferroptosis. However, AZD1775 also causes an adaptive upregulation of SLC7A11 by inhibiting the WEE1-SETDB1 axis, which enhances cellular resistance to ferroptosis.
To counteract this resistance, the researchers combined AZD1775 with actinomycin D, a nucleolar stress inducer that downregulates SLC7A11 through the p53-SLC7A11 axis. The combined treatment not only reversed the upregulation of SLC7A11 but also enhanced ferroptosis, leading to more effective suppression of tumor growth in vitro and in vivo.
Interestingly, previous research by the same team had identified actinomycin D as a potent promoter of ferroptosis by activating the nucleolar stress-p53 pathway, which further supports its use in combination with AZD1775 in this study. These results demonstrate the potential of utilizing nucleolar stress inducers to enhance ferroptosis in the treatment of cancer.
In their experiments, the team observed that the combination of AZD1775 and actinomycin D significantly increased the levels of reactive oxygen species (ROS) and lipid peroxidation in lung cancer cells. In xenograft mouse models, the combination therapy significantly reduced tumor growth with minimal toxicity, demonstrating its potential as a feasible treatment strategy for cancers harboring wild-type p53.
This study uncovers a novel strategy for overcoming resistance to ferroptosis by targeting SLC7A11 and proposes a combination therapy with AZD1775 and actinomycin D, offering a new therapeutic perspective for cancer patients with wild-type p53.
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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis
Journal
Science China Life Sciences