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Epigenetic priming sensitizes gastric cancer cells to irinotecan and cisplatin by restoring multiple pathways

  • Hiroshi Moro
  • Naoko Hattori
  • Yoshiaki Nakamura
  • Kana Kimura
  • Toshio Imai
  • Masahiro Maeda
  • Masakazu Yashiro
  • Toshikazu UshijimaEmail author
Original Article
First Online:
  • 230 Downloads

Abstract

Background

Gastric cancer is heavily influenced by aberrant DNA methylation that alters multiple cancer-related pathways, and may respond to DNA demethylating agents, such as 5-aza-2′-deoxycytidine (5-aza-dC). Here, we aimed to analyze whether 5-aza-dC can sensitize gastric cancer cells to clinically used cytotoxic drugs.

Methods

Ten gastric cancer cell lines were treated with 5-aza-dC for 72 h and their growth was analyzed by conducting WST assay. In vivo effect of the drugs was analyzed using xenografts of OCUM-2 M/SN38 cells. Genome-wide expression and DNA methylation analyses were conducted using microarrays, and biological functions were identified through ingenuity pathway analysis.

Results

The cell lines most resistant to SN38 (an active metabolite of irinotecan), CDDP, PTX, and 5-FU, were identified. 5-Aza-dC pre-treatment of the resistant cell lines decreased the IC50 values for SN38 (TMK1, 226.4 nM to 32.91 nM; 44As3, 128.2 nM to 19.32 nM; OCUM2 M/SN38, 74.43 nM to 16.47 nM) and CDDP (TMK1, 5.05 µM to 2.26 µM; OCUM2 M, 10.79 µM to 2.77 µM), but not PTX and 5-FU. The reactivation of apoptosis-related genes, such as RUNX3, PYCARD, TNF, FAS, and FASLG, was induced by pre-treatment with 5-aza-dC, and the DNA demethylation of promoter CpG islands of RUNX3 and PYCARD was confirmed. In a xenograft model with OCUM2 M/SN38, treatment with 5-aza-dC before irinotecan showed markedly enhanced tumor suppression.

Conclusion

Epigenetic priming with 5-aza-dC can improve the sensitivity of gastric cancer cells to SN38 and CDDP.

Keywords

DNA methylation Resistance Decitabine Irinotecan Cisplatin 
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Notes

Funding

This study was supported by AMED under grant number JP19ck0106421.

Compliance with ethical standards

Conflicts of interest

T. U. has received a research grant from Ohara Pharmaceutical Co, Ltd. The other authors declare that they have no conflict of interest.

Ethical approval

All institutional and national guidelines for the care and use of laboratory animals were followed.

Supplementary material

10120_2019_1010_MOESM1_ESM.pdf (105 kb)
Supplementary material 1 (PDF 105 kb)

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  1. 1.Division of EpigenomicsNational Cancer Center Research InstituteTokyoJapan
  2. 2.Course of Advanced Clinical Research of CancerJuntendo University Graduate School of MedicineTokyoJapan
  3. 3.Department of Gastroenterology and Gastrointestinal OncologyNational Cancer Center Hospital EastChibaJapan
  4. 4.Central Animal DivisionNational Cancer Center Research InstituteTokyoJapan
  5. 5.Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan

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