Natural compound library screening identifies Sanguinarine chloride for the treatment of SCLC by upregulating CDKN1A

Abstract

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.

Keywords

• Natural compound
• SCLC
• Sanguinarine chloride
• Panobinostat
• CDKN1A