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Raddeanin A exerts potent efficacy against non-small cell lung cancer by inhibiting cyclin-dependent kinase 6
Xian Wang1, Xiao Lin2, Yuxin Liu2
1Pulmonary Division, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Shanghai Fengxian District Central Hospital, No. 6600, Nanfeng Highway, Fengxian District, Shanghai 201499, China.
Purpose:
The aim of this study was to investigate the anti-tumor effects and mechanisms of Raddeanin A in NSCLC in vitro and in vivo.
Methods:
The effects of Raddeanin A on cell cycle progression, proliferation, migration and invasion of NSCLC were assessed by flow cytometry and cell biological assays in multiple NSCLC cell lines. To identify possible targets of Raddeanin A in NSCLC, we employed a multifaceted approach incorporating network pharmacology, molecular docking, and molecular dynamics simulation, along with additional techniques such as SPR (Surface Plasmon Resonance), Co-IP (Co-Immunoprecipitation), and immunofluorescence. In vivo effects were investigated using a nude mouse xenograft tumor model.
Results:
Raddeanin A inhibits NSCLC cell survival, inhibits invasion and migration and causes cell cycle arrest in G1 phase. Raddeanin A impacts NSCLC cellular activity by inhibiting CDK6, leading to anti-tumor effects. Molecular analysis confirms that the tight binding between Raddeanin A and CDK6, facilitated by specific hydrogen bonds at binding sites including VAL-101, HIS-100, GLN-149, LYS-147, THR-182, VAL-180, and ALA-23, stabilizes within the 40-100 ns interval. In a nude mouse xenograft tumor model, Raddeanin A also demonstrated an inhibitory effect on NSCLC tumor growth.
Conclusions:
Raddeanin A blocks the cell cycle in G1 phase by inhibiting CDK6. Raddeanin A is expected to be a novel antitumor agent against NSCLC.
Insights
Raddeanin A effectively inhibits non-small cell lung cancer (NSCLC) growth by halting cell cycle progression. This natural compound shows promise as a novel therapeutic agent for NSCLC treatment.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide.
- Developing novel therapeutic agents with improved efficacy and reduced toxicity is crucial for effective NSCLC treatment.
Purpose of the Study:
- To investigate the anti-tumor effects and underlying mechanisms of Raddeanin A in NSCLC.
- To evaluate the efficacy of Raddeanin A both in vitro and in vivo.
Main Methods:
- Assessed Raddeanin A's effects on NSCLC cell cycle, proliferation, migration, and invasion using flow cytometry and cell biological assays.
- Employed network pharmacology, molecular docking, molecular dynamics, SPR, Co-IP, and immunofluorescence to identify Raddeanin A's molecular targets.
- Evaluated in vivo anti-tumor effects using a nude mouse xenograft tumor model.
Main Results:
- Raddeanin A significantly inhibited NSCLC cell survival, invasion, and migration, inducing G1 phase cell cycle arrest.
- Identified Cyclin-Dependent Kinase 6 (CDK6) as a key target, with Raddeanin A demonstrating tight binding and inhibition of CDK6.
- Confirmed Raddeanin A's inhibitory effect on NSCLC tumor growth in a preclinical in vivo model.
Conclusions:
- Raddeanin A effectively blocks the G1 phase cell cycle by inhibiting CDK6.
- Raddeanin A exhibits significant anti-tumor activity against NSCLC, positioning it as a potential novel therapeutic agent.
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