2022 Fiscal Year Final Research Report
Development of adjuvant for treatment of hormone-dependent cancers targeted to aldo-keto reductases
| Project/Area Number |
20K07033
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Gifu Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | アルドケト還元酵素 / 薬剤耐性 / 乳がん / 前立腺がん |
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| Outline of Final Research Achievements |
In this study, I found that expression of aldo-keto reductase (AKR) 1C3 is up-regulated by resistance development to drugs [tamoxifen (TAM) and paclitaxel (PTX)] in hormone-dependent cancers such as breast cancer. In addition, the development of breast cancer cell resistance to TAM and PTX enhanced the capacities underlying antioxidant functions and drug effluxes, respectively. Furthermore, combined treatment of inhibitors (that block the antioxidant and drug-efflux capacities) with AKR1C3 inhibitor overcame the drug resistance, suggesting the availability of combination of the inhibitors in adjuvant therapy for alleviating the drug resistance in hormone-dependent cancers. Additionally, it is surmised that sensitization to cisplatin due to treatment with AKR1C3 inhibitor allows for off-label use of the platinum drug in breast cancer chemotherapy.
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| Free Research Field |
病態生化学
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| Academic Significance and Societal Importance of the Research Achievements |
我が国において罹患者数が年々増加している乳がん等のホルモン依存性がんは、概して薬剤感受性が低い上、連続投与に伴って容易に耐性化するため、薬剤耐性化を誘起しない画期的治療法の開発は急務である。本研究を通して、乳がんの薬剤耐性時に高発現するアルドケト還元酵素 (AKR) 1C3が薬剤耐性を誘発する主因であることを示した。また、本酵素の阻害剤を主軸とした他阻害剤との併用はホルモン依存性がんの薬剤耐性を抑制するアジュバント療法として有効であること、並びに乳がん化学療法への白金製剤の適応外使用を可能にすることを示唆した。本研究の更なる進展はホルモン依存性がんの根本治療法の確立に繋がると考えられる。
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