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Rosmarinic acid in combination with ginsenoside Rg1 suppresses colon cancer metastasis via co-inhition of COX-2 and PD1/PD-L1 signaling axis

Acta Pharmacologica Sinica volume 45, pages 193–208 (2024)Cite this article

Abstract

Metastasis of colorectal cancer (CRC) is a leading cause of mortality among CRC patients. Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells. Although COX-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy, their toxicity and variable therapeutic effects in individual patients raise concerns. To address this challenge, it is vital to identify traditional Chinese medicine components that modulate COX-2 and PD-1/PD-L1: rosmarinic acid (RA) exerts striking inhibitory effect on COX-2, while ginsenoside Rg1 (GR) possesses the potential to suppress the binding of PD-1/PD-L1. In this study we investigated whether the combination of RA and GR could exert anti-metastatic effects against CRC. MC38 tumor xenograft mouse model with lung metastasis was established. The mice were administered RA (100 mg·kg−1·d−1, i.g.) alone or in combination with GR (100 mg·kg−1·d−1, i.p.). We showed that RA (50, 100, 150 μM) or a COX-2 inhibitor Celecoxib (1, 3, 9 μM) concentration-dependently inhibited the migration and invasion of MC38 cells in vitro. We further demonstrated that RA and Celecoxib inhibited the metastasis of MC38 tumors in vitro and in vivo via interfering with the COX-2-MYO10 signaling axis and inhibiting the generation of filopodia. In the MC38 tumor xenograft mice, RA administration significantly decreased the number of metastatic foci in the lungs detected by Micro CT scanning; RA in combination with GR that had inhibitory effect on the binding of PD-1 and PD-L1 further suppressed the lung metastasis of colon cancer. Compared to COX-2 inhibitors and immune checkpoint inhibitors, RA and GR displayed better safety profiles without disrupting the tissue structures of the liver, stomach and colon, offering insights into the lower toxic effects of clinical traditional Chinese medicine against tumors while retaining its efficacy.

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Fig. 1: RA inhibits colon cancer metastasis in vitro and in vivo.
Fig. 2: RA inhibits colon cancer metastasis via COX-2 – MYO10 axis.
Fig. 3: COX-2 and MYO10 are highly expressed in human colon cancer.
Fig. 4: Knockout of COX-2 reduces MYO10 expression and inhibits MC38 cell migration and invasion.
Fig. 5: RA can inhibit the migration and invasion abilities of Ptgs2OE MC38 cells.
Fig. 6: RA combined with GR can further inhibit colon cancer metastasis in vivo.
Fig. 7: GR could activate CD8 T cells.
Fig. 8: Mechanism diagram.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81973734, 81961128020 and 82204802), the Jiangsu Specially Appointed Professorship Foundation (013038021001) and the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX22_2014).

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  1. These authors contributed equally: Huan Liu, Rui Deng

Authors and Affiliations

  1. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Huan Liu, Rui Deng, Cheng-wei Zhu, Hong-kuan Han, Gang-fan Zong, Lang Ren, Peng Cheng, Zhong-hong Wei & Yin Lu

  2. State Key Laboratory Cultivation Base for Traditional Chinese Medicine (TCM) Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Zhong-hong Wei & Yin Lu

  3. School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Yang Zhao & Su-yun Yu

  4. Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Yin Lu

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Contributions

HL and RD performed most of the experiments and analyzed the data. CWZ, GFZ and HKH participated in part of the experiments. LR, PC and ZHW provided helps for the statistical analysis. YZ, SYY, and YL conceived supervised the study. HL and SYY wrote the manuscript.

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Correspondence to Yang Zhao, Su-yun Yu or Yin Lu.

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Liu, H., Deng, R., Zhu, Cw. et al. Rosmarinic acid in combination with ginsenoside Rg1 suppresses colon cancer metastasis via co-inhition of COX-2 and PD1/PD-L1 signaling axis. Acta Pharmacol Sin 45, 193–208 (2024). https://doi.org/10.1038/s41401-023-01158-8

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