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Griseofulvin Radiosensitizes Non-Small Cell Lung Cancer Cells and Activates cGAS
Xing Wang1,2, Natasha Raman1, Ghali Lemtiri-Chlieh1
1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
Molecular Cancer Therapeutics
|February 8, 2023
Summary
Griseofulvin (GF) inhibits centrosome clustering (CC), enhancing radiation therapy (RT) efficacy in non-small cell lung cancer (NSCLC) models. This combination therapy shows promise for treating lung cancer, potentially through immune system activation.
Area of Science:
- Oncology
- Cell Biology
- Cancer Research
Background:
- Extra centrosomes are common in cancer cells, enabling proliferation through centrosome clustering (CC).
- Centrosome clustering inhibition (CCi) presents a potential strategy to target cancer cells.
- Non-small cell lung cancer (NSCLC) exhibits centrosome amplification, suggesting CCi as a therapeutic avenue.
Purpose of the Study:
- To investigate if centrosome clustering inhibition (CCi) radiosensitizes non-small cell lung cancer (NSCLC).
- To evaluate the efficacy of Griseofulvin (GF), an FDA-approved CC inhibitor, in combination with radiation treatment (RT) for NSCLC.
Main Methods:
- In vitro studies using NSCLC cell lines treated with GF and RT.
- In vivo studies involving mouse models of NSCLC treated with GF and RT.
- Assessment of mitotic spindle formation, cell viability, colony formation, micronuclei (MN) generation, and cGAS-STING pathway activation.
Main Results:
- GF combined with RT significantly increased multipolar spindles, decreased NSCLC cell viability and colony formation in vitro.
- GF treatment was well-tolerated in vivo, and GF + RT significantly delayed tumor growth.
- Both GF and RT induced micronuclei (MN) and activated cyclic GMP-AMP synthase (cGAS); combination therapy enhanced cGAS-STING pathway activation in radioresistant A549 cells.
Conclusions:
- Griseofulvin enhances radiation treatment efficacy in preclinical NSCLC models.
- The observed radiosensitization may be linked to micronuclei generation and cGAS activation.
- Combination therapy of CCi, RT, and immunotherapy represents a promising strategy for NSCLC treatment.
