Epigenetic priming sensitizes gastric cancer cells to irinotecan and cisplatin by restoring multiple pathways
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ORIGINAL ARTICLE
Epigenetic priming sensitizes gastric cancer cells to irinotecan and cisplatin by restoring multiple pathways Hiroshi Moro1,2 · Naoko Hattori1 · Yoshiaki Nakamura1,3 · Kana Kimura1 · Toshio Imai4 · Masahiro Maeda1 · Masakazu Yashiro5 · Toshikazu Ushijima1,2 Received: 27 June 2019 / Accepted: 2 September 2019 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019
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
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-019-01010-1) contains supplementary material, which is available to authorized users. * Toshikazu Ushijima [email protected] 1
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
2
Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan
3
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
4
Central Animal Division, National Cancer Center Research Institute, 5‑1‑1 Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan
5
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
Cancer is caused by irreversible changes of gene function, namely genetic and epigenetic alterations [1]. Between these two kinds of alterations, gastric cancer is more heavily influenced by epigenetic alterations,
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