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Published on: January 22, 2019
Natural compound library screening identifies Sanguinarine chloride for the treatment of SCLC by upregulating CDKN1A
Mingtian Zhong1, Xun Li1, Fengyun Zhao2
1Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; Institute for Brain Research and Rehabilitation, South China Normal University, Tianhe District, Guangzhou, Guangdong 510631, China.
Objectives:
Small cell lung cancer (SCLC) is notorious for aggressive malignancy without effective treatment, and most patients eventually develop tumor progression with a poor prognosis. There is an urgent need for discovering novel antitumor agents or therapeutic strategies for SCLC.
Materials And Methods:
We performed a screening method based on CCK-8 assay to screen 640 natural compounds for SCLC. The effects of Sanguinarine chloride on SCLC cell proliferation, colony formation, cell cycle, apoptosis, migration and invasion were determined. RNA-seq and bioinformatics analysis was performed to investigate the anti-SCLC mechanism of Sanguinarine chloride. Publicly available datasets and samples were analyzed to investigate the expression level of CDKN1A and its clinical significance. Loss of functional cancer cell models were constructed by shRNA-mediated silencing. Quantitative RT-PCR and Western blot were used to measure gene and protein expression. Immunohistochemistry staining was performed to detect the expression of CDKN1A, Ki67, and Cleaved caspase 3 in xenograft tissues.
Results:
We identified Sanguinarine chloride as a potential inhibitor of SCLC, which inhibited cell proliferation, colony formation, cell cycle, cell migration and invasion, and promoted apoptosis of SCLC cells. Sanguinarine chloride played an important role in anti-SCLC by upregulating the expression of CDKN1A. Furthermore, Sanguinarine chloride in combination with panobinostat, or THZ1, or gemcitabine, or (+)-JQ-1 increased the anti-SCLC effect compared with either agent alone treatment.
Conclusions:
Our findings identified Sanguinarine chloride as a potential inhibitor of SCLC by upregulating the expression of CDKN1A. Sanguinarine chloride in combination with chemotherapy compounds exhibited strong synergism anti-SCLC properties, which could be further clinically explored for the treatment of SCLC.
Insights
Sanguinarine chloride shows promise in treating small cell lung cancer (SCLC) by inhibiting tumor growth and promoting cell death. It works by increasing CDKN1A expression and may be effective in combination therapies for SCLC.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Small cell lung cancer (SCLC) is an aggressive malignancy with limited effective treatment options.
- Tumor progression and poor prognosis are common in SCLC patients, highlighting the need for novel therapeutic strategies.
- Discovering new antitumor agents is crucial for improving SCLC patient outcomes.
Purpose of the Study:
- To screen natural compounds for potential SCLC inhibitors.
- To investigate the anti-SCLC effects and underlying mechanisms of Sanguinarine chloride.
- To evaluate the clinical significance of CDKN1A in SCLC.
Main Methods:
- A CCK-8 assay was used to screen 640 natural compounds for SCLC activity.
- Sanguinarine chloride's effects on SCLC cell proliferation, apoptosis, and invasion were assessed.
- RNA-seq, bioinformatics, and immunohistochemistry were employed to elucidate the anti-SCLC mechanism involving CDKN1A.
Main Results:
- Sanguinarine chloride demonstrated significant inhibition of SCLC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis.
- The anti-SCLC activity of Sanguinarine chloride was attributed to the upregulation of CDKN1A expression.
- Combination therapy with Sanguinarine chloride and other agents (panobinostat, THZ1, gemcitabine, or (+)-JQ-1) showed synergistic anti-SCLC effects.
Conclusions:
- Sanguinarine chloride is identified as a potential SCLC inhibitor via CDKN1A upregulation.
- Combined Sanguinarine chloride with chemotherapy compounds exhibits strong synergistic anti-SCLC properties.
- These findings suggest Sanguinarine chloride holds potential for clinical exploration in SCLC treatment.
