Nitidine chloride induces caspase 3/GSDME-dependent pyroptosis by inhibting PI3K/Akt pathway in lung cancer
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Fei Yu1, Weidan Tan1, Zhiquan Chen1
1Department of Pharmacology, School of Pharmacy, 406 Graduate School of Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China.
Background:
As the increasing mortality and incidence of lung cancer (LC), there is an urgent need to discover novel treatment agent. In this study, we aimed to investigate the anti-LC effects of nitidine chloride (NC), a small molecular compound extracted from Chinese herbal medicine, while detailing its underlying mechanisms.
Methods:
Cell viability was detected by MTT assays and five cell death inhibitors, including ferrostatin-1 (Fer-1), Z-VAD-FMK, necrostatin-1 (Nec-1), disulfiram (DSF) and IM-54 were used to explore the type of cell death induced by NC. The microscopic features of NC-induced pyroptosis were assessed by transmission electron microscopy (TEM) and the pyroptotic-related proteins such as caspase and gasdermin family, were examined by western blot. Network pharmacology was employed to predict the potential mechanisms of NC in lung cancer treatment. CETSA and DARTs were used to determine the activity of NC binding to targeted protein. Xenograft mice model was established to further investigate the inhibitory effect and mechanism of NC against LC.
Results:
The pyroptosis inhibitor (DSF) and apoptosis inhibitor (Z-VAD-FMK) but not IM-54, necrostatin-1, or Ferrostatin-1 rescued NC-induced cell death. Morphologically, H1688 and A549 cells treated with NC showed notably pyroptotic features, such as cell swelling and large bubbles emerging from the plasma membrane. Gasdermin E (GSDME) rather than GSDMC or GSDMD was cleaved in NC-treated H1688 and A549 cells with an increased cleavage of caspase 3. Combined with network pharmacology and molecule docking, PI3K/Akt signaling axis was predicted and was further verified by CETSA and DARTs assay. In addition, the activation of PI3K is able to rescue the pyroptosis induced by NC in vitro. In xenograft model of LC, NC significantly hindered the transduction of PI3K-AKT pathway, inducing pyroptosis of tumor.
Conclusion:
Our data indicated that NC is a potential therapeutic agent for the treatment of LC via triggering GSDME-dependent pyroptosis.
Insights
Nitidine chloride (NC) shows potential as a lung cancer treatment by inducing pyroptosis, a form of programmed cell death. This study details NC
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer (LC) presents a growing global health challenge with increasing mortality and incidence.
- Novel therapeutic agents are urgently needed to combat lung cancer effectively.
- Nitidine chloride (NC), a natural compound, is explored for its anti-cancer properties.
Purpose of the Study:
- To investigate the anti-lung cancer effects of nitidine chloride (NC).
- To elucidate the underlying molecular mechanisms of NC's action in lung cancer.
- To determine the specific type of cell death induced by NC.
Main Methods:
- Cell viability assays (MTT) and cell death inhibitor screening.
- Morphological analysis of cell death using transmission electron microscopy (TEM).
- Western blot analysis of pyroptosis-related proteins (caspase, gasdermin family).
- Network pharmacology, molecular docking, CETSA, and DARTs for mechanism prediction and validation.
- In vivo studies using a xenograft mice model.
Main Results:
- NC-induced cell death was identified as pyroptosis, specifically dependent on GSDME cleavage and caspase-3 activation.
- The PI3K/Akt signaling pathway was identified as a key mediator, with NC inhibiting its activation.
- NC demonstrated significant tumor growth inhibition in a xenograft mouse model by inducing pyroptosis.
Conclusions:
- Nitidine chloride (NC) effectively triggers GSDME-dependent pyroptosis in lung cancer cells.
- NC exhibits potential as a therapeutic agent for lung cancer treatment.
- The PI3K/Akt pathway is a critical target for NC's anti-lung cancer activity.
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