4.6 Article

Inhibition of NLRP3 inflammasome activation in myeloid-derived suppressor cells by andrographolide sulfonate contributes to 5-FU sensitization in mice

Journal

TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 428, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2021.115672

Keywords

Andrographolide sulfonate; 5-FU; NLRP3; MDSCs

Funding

  1. National Natural Science Foundation of China [81871944, 81730100, 82073856]
  2. Fundamental Research Funds for the Central Universities [020814380160]
  3. Zhejiang University special scientific research fund for COVID-19 prevention and control [2020XGZX007]

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Andrographolide sulfonate, a traditional Chinese medicine, when combined with 5-FU, significantly inhibits colorectal cancer growth, promotes apoptosis, and enhances antitumor immunity by inhibiting 5-FU induced NLRP3 activation in MDSCs. This synergistic effect provides a novel strategy to address 5-FU resistance in the treatment of CRC.
5-Fluorouracil (5-FU)-based chemotherapy is the first-line recommended regimen in colorectal cancer (CRC), but resistance limits its clinical application. Andrographolide sulfonate, a traditional Chinese medicine, is mainly used to treat infectious diseases. In the present study, we reported that andrographolide sulfonate could significantly inhibit the growth of transplanted CT26 colon cancer in mice and improve survival when combined with 5-FU. Furthermore, TUNEL assay and immunohistochemistry analysis of proliferating cell nuclear antigen, Ki-67 and p-STAT3 confirmed that co-treatment could inhibit tumor proliferation and promote apoptosis. In tumor tissues of groups that received 5-FU and andrographolide sulfonate, CD4(+) and CD8(+) T cell infiltration was increased, and the expression of IFN-gamma and Granzyme B detected by immunohistochemistry and qPCR was upregulated, reflecting improved antitumor immunity. Finally, we verified that 5-FU significantly activated the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in myeloid-derived suppressor cells (MDSCs) and that andrographolide sulfonate reversed this process to sensitize cells to 5-FU. In summary, andrographolide sulfonate synergistically enhanced antitumor effects and improved antitumor immunity by inhibiting 5-FU induced NLRP3 activation in MDSCs. These findings provide a novel strategy to address 5-FU resistance in the treatment of CRC.

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