Silybin exerts therapeutic efficacy in non-small cell lung cancer by targeting Skp2

Oncology & Oncogenics, Pharmacology & Taxicology
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Shi-Bing Zhang# Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China++Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China

Ming Hong# Institute of Advanced Diagnostic and Clinical Medicine, Zhongshan People's Hospital, Zhongshan 528403, China

Xiao-Yang Sun Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Da Huang Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Dan-Hua He Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Yu-Fei Chen Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Yong Yuan* Institute of Advanced Diagnostic and Clinical Medicine, Zhongshan People's Hospital, Zhongshan 528403, China

Yong-Qiang Liu* Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

# contributed equally to this work


Abstract

Silybin (SB), a natural flavonoid isolated from Silybum Marianum, has been clinically used to treat hepatic fibrosis and also used as a dietary supplement owing to its hepatoprotective potentials. Numerous studies have shown that SB also exerts promising anticancer property; however, the anticancer targets of SB and the underlying mechanism remain unclear. In our study, we found that SB significantly inhibited the proliferation of non-small cell lung cancer (NSCLC), without causing cytotoxicity toward normal bronchial epithelial cells Beas-2B. Mechanistically, SB can bind to F-box protein Skp2 and disrupt Skp1-Skp2 interaction, thereby decreasing the protein level of Skp2 and inducing the accumulation of its substrates, leading to cell-cycle G1 phase arrest and cell migration suppression. In lung orthotopic xenografts, SB also significantly decreased Skp2 expression while increased p27/Kip1 (p27) protein level. SB administration inhibited tumor growth and metastasis in the lung tissue, prolonging the survival time of the mice without causing obvious toxicity. Taken together, SB can be considered a Skp2-targeting agent that warrants further clinical investigation.

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