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ファイル
言語
英語
著者
内容記述(抄録等)
Chemotherapy and radiotherapy are the most common approaches in cancer therapy. They may kill cancer cells through the generation of high levels of reactive oxygen species (ROS), which leads to oxidative DNA damage. However, tumor resistance to ROS is a problem in cancer therapy. MTH1 sanitizes oxidized dNTP pools to prevent the incorporation of damaged bases during DNA replication. Although MTH1 is non‑essential in normal cells, cancer cells require MTH1 activity to avoid the incorporation of oxidized dNTPs, which would result in DNA damage and cell death. By targeting a redox‑adaptation mechanism, MTH1 inhibition represents a novel therapeutic strategy against cancer. However, recent reports have indicated that growth inhibition by MTH1 inhibitors may be due to off‑target cytotoxic effects. TH588, one of the first‑in‑class MTH1 inhibitors, kills cancer cells by an off‑target effect. However, a low concentration of TH588 may effectively inhibit MTH1 activity without inhibiting cell proliferation. Phenethyl isothiocyanate (PEITC) is a dietary anticarcinogenic compound and an inducer of ROS. In the present study, it has been demonstrated that combined treatment with PEITC and TH588 effectively inhibited the growth of pancreatic cancer MIAPaCa‑2 and Panc‑1 cells. The antioxidant N‑acetylcysteine negated this synergistic growth inhibition. PEITC and TH588 cooperatively induced the formation of 8‑oxo‑deoxyguanine in nuclei and pH2AX foci, a marker of DNA damage. However, the combined effects are not associated with MTH1 mRNA expression in several cancer cell lines, suggesting that the possibility of an off‑target effect of TH588 cannot be eliminated. These results suggest that the combination of PEITC and TH588 has potential as a novel therapeutic strategy against pancreatic cancer.
主題
MTH1
TH588
phenethyl isothiocyanate
ROS inducer
oxidative DNA damage
pancreatic cancer cells
掲載誌名
ONCOLOGY LETTERS
15
開始ページ
3240
終了ページ
3244
ISSN
17921074
ISSN(Online)
17921082
発行日
2017-12-13
DOI
出版者
Spandidos Publications
資料タイプ
学術雑誌論文
ファイル形式
PDF
著者版/出版社版
出版社版
業績ID
e34680
部局
医学部