Development of tumor-selective drug based on synthetic lethal strategy by overcoming oxidative stress tolerance of cancer
| Project/Area Number |
16H05102
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Gifu Pharmaceutical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
平山 祐 岐阜薬科大学, 薬学部, 准教授 (10600207)
辻 美恵子 岐阜薬科大学, 薬学部, 助教 (40709721)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
Fiscal Year 2018: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2016: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
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| Keywords | がん微小環境 / 酸化ストレス / 小胞体ストレス応答 / 二価鉄 / 蛍光イメージング / フェロトーシス / エネルギー代謝 / 鉄代謝 / 小胞体ストレス / がん / 微小環境 / 創薬 / 酸化ストレス耐性解除 / 合成致死 / がん治療薬 / 鉄レドックス変動 |
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| Outline of Final Research Achievements |
The purpose of this study is to develop therapeutic agents that reduce stress tolerance of cancer and induce cell death selectively in cancer. Strategies for suppression of oxidative stress resistance include inhibition of mitochondrial respiration, suppression of cellular antioxidant systems, and inhibition of HIF-1 signaling and unfolded protein response (UPR) signaling pathway. 1) We have developed novel biguanide derivatives that selectively show cytotoxicity under glucose-deprived conditions. 2) We succeeded to visualize the reductive shift of iron redox equilibrium in tumor cells under the hypoxic condition and the labile iron distribution during ferroptosis using our original ferrous iron fluorescent probe. 3) It has been found that ferrotosis inducers significantly sensitized the effects of chemotherapeutic agents for resistance ovarian cancer and uterine cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
がん細胞がストレス環境に適応して生存するしくみに着目して、ストレス耐性を減弱させて治療抵抗性を改善するようながん治療薬の開発を目指した。特にがん細胞は、強い酸化ストレスにさらされながらも抵抗する仕組みをもっている。がん細胞のこのように劣悪な生存環境におけるストレス耐性を選択的に弱めることで、がん細胞選択的に障害を与えることができる。このようなくすりは、既存の癌治療法と併用することで、再発予防や予後の改善にも役立つと期待される。がんの罹患率が50%を越えた高齢化社会において希求されている、患者のQOLを損なわない新しいがん治療薬の開発に関する重要な知見が得られたものと考えられる。
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Report
(4 results)
Research Products
(68 results)
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[Journal Article] Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice2017
Author(s)
Yasumasa Ikeda, Yuya Horinouchi, Hirofumi Hamano, Tasuku Hirayama, Seiji Kishi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Ken-ichi Aihara, Hideko Nagasawa, Koichiro Tsuchiya, and Toshiaki Tamaki
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Journal Title
Scientific Reports
Volume: 7
Issue: 1
Pages: 10621-10621
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Role of catalytic iron and oxidative stress in nitrofen-induced congenital diaphragmatic hernia and its amelioration by Saireito (TJ-114)2017
Author(s)
Hirako, S., Tsuda, H., Ito, F., Okazaki, Y., Hirayama, T., Nagasawa, H., Nakano, T., Imai, K., Kotani, T,. F., Kikkawa, Toyokuni, S.
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Journal Title
Journal of Clinical Biochemistry and Nutrition
Volume: 61
Issue: 3
Pages: 176-182
DOI
NAID
ISSN
0912-0009, 1880-5086
Related Report
Peer Reviewed / Open Access
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[Journal Article] Non-Thermal Plasma Induces a Stress Response in Mesothelioma Cells Resulting in Increased Endocytosis, Lysosome Biogenesis and Autophagy.2017
Author(s)
Shi. L., Ito, F., Wang, Y., Okazaki, Y., Tanaka, H., Mizuno, M., Hori. M., Hirayama, T., Nagasawa, H., Richardson, Des R, Toyokuni, S.
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Journal Title
Free Radic. Biol. Med.
Volume: 108
Pages: 904-917
DOI
NAID
Related Report
Peer Reviewed / Int'l Joint Research
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