2018 Fiscal Year Final Research Report
Hypotonic stimulation enhances paclitaxel uptake into cancer cells via regulation of aquaporin
| Project/Area Number |
17K16576
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Digestive surgery
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
Kosuga Toshiyuki 京都府立医科大学, 医学(系)研究科(研究院), 助教 (00457946)
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Keywords | 癌 / アクアポリン / 低浸透圧刺激 / 調節性細胞容積減少 / パクリタキセル |
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| Outline of Final Research Achievements |
At first, we confirmed that hypotonic stimulation enhanced paclitaxel (PTX) uptake into MKN45 cells (human GC cell line) with increasing their cell volume. The mRNA expressions of influx (OATP1B3) and efflux (MDR1) transporters for PTX were not changed by hypotonic stimulation, and the blockade of OATP1B1/3 with rifampicin did not affect hypotonicity-induced PTX uptake into GC cells; thus, hypotonic stimulation did not alter the expression and function of transporters for PTX. Next, we examined the influence of the expression and function of aquaporin 5 (AQP5) on hypotonicity-induced PTX uptake into GC cells. Neither the blockade of AQP5 with HgCl2 nor the knockdown of AQP5 using AQP5-siRNA affected hypotonicity-induced cellular uptake of PTX. Meanwhile, the blockade of chloride transports with NPPB inhibited the occurrence of regulatory volume decrease (RVD), and significantly enhanced PTX uptake into GC cells.
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| Free Research Field |
消化器外科学
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| Academic Significance and Societal Importance of the Research Achievements |
腹腔内パクリタキセル投与は、難治性の胃癌・膵癌腹膜播種性転移に対する新たな治療選選択の一つとして注目されているが、浸透圧・イオン輸送体・水輸送体制御による治療効果増強や、その分子生物学的・細胞生理学的メカニズムについての研究報告は存在しない。本研究は、低浸透圧刺激併用による腹腔内パクリタキセル投与療法という新しい治療概念を構築するとともに、クロライドイオン輸送阻害薬併用によるRVD抑制を介した低浸透圧細胞内PTX取り込み増強効果という全く新たな知見を明らかにしたという点で、学術的・社会的に意義があると思われる。
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