2. Academic Validation
  3. Asiatic acid reverses cisplatin resistance in A549/DDP cells by activating the P38 MAPK/Slug pathway

Asiatic acid reverses cisplatin resistance in A549/DDP cells by activating the P38 MAPK/Slug pathway

  • Tissue Cell. 2025 Sep 17:98:103145. doi: 10.1016/j.tice.2025.103145.
Min Yu 1,  Qian Zhang 2,  Wenli Shang 2,  Shenghong Wei 2,  Hongxia Wen 2,  Shufen Huo 2,  Xiang Li 3,  Xuan Li 3,  Heng Zhang 4,  Yingxuan Tian 5
Affiliations

Affiliations

  • 1 Department of Internal Medicine-Oncology, Shaanxi Provincial People's Hospital, Shaanxi 710068, China.
  • 2 Department of Geriatric Respiratory, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China.
  • 3 Graduate School of Medical College of Yan'an University, Yan'an University, Yan'an, Shaanxi 710068, China.
  • 4 Department of Geriatric Medicine, The Affiliated Shaanxi Provincial People's Hospital, Xi'an Medical College, Xi'an, Shaanxi 710068, China.
  • 5 Department of Geriatric Respiratory, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, China; Department of Geriatric Medicine, The Affiliated Shaanxi Provincial People's Hospital, Xi'an Medical College, Xi'an, Shaanxi 710068, China. Electronic address: YingxuanTiantyt@finmail.com.
PMID: 41014726 DOI: 10.1016/j.tice.2025.103145
Abstract

Background: Drug resistance has become a major challenge in the treatment of non-small cell lung Cancer (NSCLC). A promising therapeutic approach involves the identification of potent resistance modulators and their combined application with conventional chemotherapeutic agents. Asiatic acid (AA), a bioactive pentacyclic triterpenoid derived from the medicinal plant Centella asiatica, has shown significant Anticancer properties in various studies. This study aims to evaluate the molecular mechanisms by which AA affects cisplatin (DDP)-resistant lung Cancer A549/DDP cells.

Methods: The optimal concentrations of AA and DDP for A549 and A549/DDP cells were initially identified using the CCK-8. Following this, AA's impact on A549/DDP cells was evaluated in vitro, while resistance mechanisms were investigated via molecular docking and verified using pathway inhibitors. Furthermore, a nude mice lung Cancer xenograft model was established to investigate the impact of AA on tumor growth in vivo.

Results: AA may enhance the sensitivity of A549/DDP cells to DDP by inhibiting the levels of P-gp, MVP, and Bcl-2, while promoting the levels of Bax and Caspase-3. Molecular docking and in vitro experiments demonstrated that AA forms stable interactions with p-p38 MAPK, P-gp, and Slug, and reduces Slug-mediated resistance pathways by inhibiting the phosphorylation of p38 MAPK. This ultimately increases the sensitivity of NSCLC cells to DDP. The p38 MAPK Inhibitor Doramapimod partially reversed this effect. In vivo experiments further showed that Doramapimod weakened the AA-mediated DDP-sensitizing effect, promoting tumor growth.

Conclusion: AA reverses cisplatin resistance in A549/DDP cells by activating the p38 MAPK/Slug pathway. The p38 MAPK Inhibitor Doramapimod partially reverses this effect.

Keywords

Asiatic acid (AA); Cisplatin (DDP) resistance; Non-small cell lung cancer (NSCLC); P38 MAPK/Slug pathway.

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