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

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.

• Authors: Hiroshi Moro, Naoko Hattori, Yoshiaki Nakamura, Kana Kimura, Toshio Imai, Masahiro Maeda, Masakazu Yashiro, Toshikazu Ushijima
• Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 23 Issue 1 Pg. 105-115 (01 2020) ISSN: 1436-3305 [Electronic] Japan
• PMID: 31555951 (Publication Type: Journal Article)

Chemical References

• Irinotecan
• Decitabine
• Cisplatin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Cisplatin (administration & dosage)
• DNA Methylation (drug effects)
• Decitabine (administration & dosage)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epigenesis, Genetic (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Irinotecan (administration & dosage)
• Mice, Nude
• Stomach Neoplasms (drug therapy, genetics)
• Xenograft Model Antitumor Assays