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Src inhibitor dasatinib sensitized gastric cancer cells to cisplatin

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Abstract

Gastric cancer (GC) is characterized by high incidence and mortality, and lacks effective treatment. Surgery, combined with chemo- and radiation therapy, represents the cornerstones of GC treatment. Although platinum is commonly used, severe side effects and drug resistance limited its application. Cisplatin-induced cell death mainly relies on the increment of reactive oxygen species (ROS), while the effect of dasatinib on ROS is inconclusive. In this article, dasatinib and cisplatin showed various anti-cancer properties on GC cells, which might be related to the changes of ROS levels. However, NAC enhanced cell death induced by dasatinib, although it elevated ROS levels in GES1 and AGS cells, suggesting that the elevation of ROS levels was not the responsible mechanism. Notably, dasatinib markedly synergized cells against cisplatin. Dasatinib decreased pSer473 Akt levels, and increased p53 expression, which was confirmed by LY294002 or Nutlin-3a co-treatment. Furthermore, transcriptome sequencing also confirmed that the PI3K/AKT pathway was involved in the anti-cancer effect of dasatinib or combined with cisplatin. Additionally, GC cells with higher Src activity (AGS) elicited more sensitive to dasatinib than lower cells (SGC7901 and MGC803), suggesting that the Src levels could be applied to pre-select patients who would benefit from dasatinib and/or combined with platinum compounds.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thanked Dr. Zheng Meijuan from Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, for her contribution for supporting us using flow cytometry to adjust our experimental condition of ROS assay at the beginning of our study.

Funding

This work was supported by Natural Science Foundation of Anhui Province (No. 2008085QH408), and National Natural Science Foundation of China (No. 81874063).

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Author notes

  1. Huizhen Wang and Yida Lu have contributed equally to this study.

Authors and Affiliations

  1. Department of General Surgery, The First Affiliated of Anhui Medical University, Hefei, 230022, China

    Huizhen Wang, Yida Lu, Mingliang Wang, Aolin Shen, Youliang Wu, Xin Xu & Yongxiang Li

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  1. Huizhen Wang
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Contributions

Conceptualization, supervision, project administration, and funding acquisition: LY, WH; methodology: WH, LY, and WM; validation: WH, SA, WY, and XX; visualization: SA, and XX; writing-original draft: WH; writing-review & editing: LY, WM, and WY.

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Correspondence to Yongxiang Li.

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Wang, H., Lu, Y., Wang, M. et al. Src inhibitor dasatinib sensitized gastric cancer cells to cisplatin. Med Oncol 40, 49 (2023). https://doi.org/10.1007/s12032-022-01879-6

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