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  2. Network pharmacology and experimental verification-based strategy for exploring the mechanisms of luteolin in the treatment of osteosarcoma

Network pharmacology and experimental verification-based strategy for exploring the mechanisms of luteolin in the treatment of osteosarcoma

  • Cancer Cell Int. 2023 Sep 25;23(1):213. doi: 10.1186/s12935-023-03046-x.
Renxuan Huang # 1 Mingxian Xu # 1 Weitang Guo 1 Mingzhe Cheng 1 Rui Dong 2 3 4 Jian Tu 1 Shao Xu 5 Changye Zou 6
Affiliations

Affiliations

  • 1 Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, 2nd Zhongshan Road, Guangzhou, 510080, China.
  • 2 Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
  • 3 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Sciences, Guangzhou, 510080, China.
  • 4 Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, 510080, China.
  • 5 Department of Stomatology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Road, Guangzhou, 510630, China. xushaozcy@aliyun.com.
  • 6 Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, 2nd Zhongshan Road, Guangzhou, 510080, China. zouchy@mail.sysu.edu.cn.
  • # Contributed equally.
Abstract

Background: Luteolin is an active ingredient in various traditional Chinese medicines for the treatment of multiple tumors. However, the mechanisms of its inhibitory effect on osteosarcoma proliferation and metastasis remain unclear.

Purpose: To elucidate the anti-osteosarcoma mechanisms of luteolin based on network pharmacology and experimental verification.

Study design: Integrate network pharmacology predictions, scRNA-seq analysis, molecular docking, and experimental validation.

Methods: Luteolin-related targets and osteosarcoma-associated targets were collected from several public databases. The luteolin against osteosarcoma targets were screened and a PPI network was constructed to identify the hub targets. The GO and KEGG enrichment of osteosarcoma-associated targets and luteolin against osteosarcoma targets were performed. And scRNA-seq analysis was performed to determine the distribution of the core target expression in OS tissues. Molecular docking, cell biological assays, and osteosarcoma orthotopic mouse model was performed to validate the inhibitory effect and mechanisms of luteolin on osteosarcoma proliferation and metastasis.

Results: Network pharmacology showed that 251 luteolin against osteosarcoma targets and 8 hub targets including Akt1, ALB, CASP3, IL6, JUN, STAT3, TNF, and VEGFA, and the PI3K-AKT signaling pathway might play an important role in anti-osteosarcoma of luteolin. Analysis of public data revealed that Akt1, IL6, JUN, STAT3, TNF, and VEGFA expression in OS tissue was significantly higher than that in normal bones, and the diagnostic value of VEGFA for overall survival and metastasis was increased over time. scRNA-seq analysis revealed significantly higher expression of Akt1, STAT3, and VEGFA in MYC+ osteoblastic OS cells, especially in primary samples. Moreover, the docking activity between luteolin and the hub targets was excellent, as verified by molecular docking. Experimental results showed that luteolin could inhibit cell viability and significantly decrease the expression of Akt1, STAT3, IL6, TNF, and VEGFA, and luteolin could also inhibit osteosarcoma proliferation and metastasis in osteosarcoma orthotopic mouse model.

Conclusion: This study shows that luteolin may regulate multiple signaling pathways by targeting various genes like Akt1, STAT3, IL6, TNF, and VEGFA to inhibit osteosarcoma proliferation and metastasis.

Keywords

Luteolin; Molecular docking; Network pharmacology; Orthotopic mouse model; Osteosarcoma; scRNA-seq.

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