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Cetuximab enhances the activities of irinotecan on gastric cancer cell lines through downregulating the EGFR pathway upregulated by irinotecan

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Abstract

Purpose

Treatment effects of advanced gastric cancer (AGC) are unsatisfactory, and novel therapeutic approaches are much needed. The epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab inhibits the growth of several human cancer cells but has been tested rarely for the treatment of GC. The synergy between cetuximab and irinotecan has been reported in colorectal cancer, but the mechanisms are still not fully clarified. Consequently, we hypothesized cetuximab/irinotecan combination should enhance the antitumor activity of irinotecan in GC cells.

Methods

The in vitro antiproliferative, pro-apoptotic, cell cycle arrest effects and induction of senescence were examined in SGC-7901 and MKN-45 GC cell lines. The effects of cetuximab or irinotecan as single agents or the combination on the expression of p53, p16, and EGFR signaling pathways were also studied.

Results

The study revealed that cetuximab alone did not show any antiproliferative, pro-apoptotic, cell cycle arrest or cellular senescence effect on GC cells but when combined with irinotecan synergistically inhibits GC cell proliferation and induces apoptosis and G2/M phase arrest. Irinotecan increases phosphorylation of EGFR, MAPK, and AKT and decreases the expression of P27Kip1, which could be all abrogated by its combination with cetuximab. The combination could also inhibit the expression of Cyclin D1 and phosphorylated mTOR while had no impact on p53, p16, PTEN, and HIF-1alpha.

Conclusions

Cetuximab enhances the activities of irinotecan on GC cells via the downregulation of the EGFR pathway upregulated by irinotecan. Combination therapy with cetuximab and irinotecan, a novel therapeutic approach, warrants further study in GC.

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Acknowledgments

We thank Xiangjin Liu, M.D. for her assistance in the medical writing of this article.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China

    Xin Liu, Wei-Jian Guo, Xiao-Wei Zhang, Shu Tian & Jin Li

  2. Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China

    Xu Cai

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Xin Liu, Wei-Jian Guo, Xiao-Wei Zhang, Xu Cai, Shu Tian & Jin Li

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  1. Xin Liu
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Correspondence to Jin Li.

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Liu, X., Guo, WJ., Zhang, XW. et al. Cetuximab enhances the activities of irinotecan on gastric cancer cell lines through downregulating the EGFR pathway upregulated by irinotecan. Cancer Chemother Pharmacol 68, 871–878 (2011). https://doi.org/10.1007/s00280-011-1559-2

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  • DOI: https://doi.org/10.1007/s00280-011-1559-2

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