| Project/Area Number |
18K14996
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Kobe Pharmaceutical University |
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Principal Investigator |
Horibe Sayo 神戸薬科大学, 薬学部, 講師 (50389110)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | シスプラチン / 耐性獲得 / ミトコンドリアDNA / ミトコンドリアDNA変異 / 抗がん剤耐性 / ミトコンドリア機能不全 |
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| Outline of Final Research Achievements |
Cisplatin (CDDP) is widely used as an anti-cancer platinum agent known to be effective in various solid tumors including lung cancer. The acquired resistance during long-term cisplatin (CDDP) administration leads to a failure of chemotherapy. CDDP preferentially adducts to mitochondrial DNA (mtDNA), which is necessary for normal mitochondrial function. We previously established human lung cancer A549 cell-derived cisplatin resistant (ACR20) cells. We found that mitochondrial function was deteriorated in ACR20 cells. Mutations in several mitochondrial DNA (mtDNA)-encoded complex Ⅰ subunits were only identified in ACR20 cells. We constructed cybrids (HeLamtA549 or HeLamtACR20) by fusing enucleated A549 cells or ACR20 cells with mtDNA-depleted ρ0HeLa cells. In HeLamtACR20 cells, IC50 of CDDP was about 2.5 times higher, complex Ⅰ activity were decreased compared with HeLamtA549 cells. The present results suggest that mtDNA mutations play a role in the acquired resistance to CDDP.
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| Academic Significance and Societal Importance of the Research Achievements |
シスプラチン（CDDP）に対する耐性を獲得する機構については、様々な原因が報告されているが、CDDPに対する感受性を評価するバイオマーカーや耐性を改善する治療薬がないのが現状である。本研究により、ミトコンドリアDNA変異によるミトコンドリア機能低下がCDDPの耐性獲得に関与することを見出した。本研究より、ミトコンドリアDNAの変異がCDDPに対する感受性のバイオマーカーの候補になる可能性を示した。
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