JP6478332B2 - p21活性化キナーゼ阻害剤 - Google Patents
p21活性化キナーゼ阻害剤 Download PDFInfo
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- JP6478332B2 JP6478332B2 JP2016134873A JP2016134873A JP6478332B2 JP 6478332 B2 JP6478332 B2 JP 6478332B2 JP 2016134873 A JP2016134873 A JP 2016134873A JP 2016134873 A JP2016134873 A JP 2016134873A JP 6478332 B2 JP6478332 B2 JP 6478332B2
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Description
C.エレガンスの野生株N2と変異株CL2070、大腸菌OP50株はC.エレガンスゲノムセンター(ミネソタ大学)から購入した。C.エレガンスPAK1欠損株(RB689株)は大東文化大学の簗瀬澄乃博士から提供を受けた。ヒト肺ガン細胞A549はJCRB細胞バンクから購入した。B16F10メラノーマ細胞及び3T3−L1細胞は、アメリカン・タイプ・カルチュア・コレクション(ATCC)から購入した。ダルベッコ改変イーグル培地(DMEM)、3−イソブチル−1−メトキシキサンチン(IBMX)、トリトンX−100、牛胎児血清(FBS)、ウシ血清アルブミン(BSA)は和光純薬工業社から購入した。抗PAK1抗体IgGは、セルシグナリングテクノロジー(ダンバース社)から購入した。レスベラトロール、3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウムブロミド(MTT),プロテインAアガロースビーズ、ミエリン塩基性タンパク質(MBP)はシグマアルドリッチ社から購入した。キナーゼGlo試薬、アデノシン三リン酸(ATP)はプロメガ社から購入した。(+)−5−フルオロ−2’−デオキシウリジン(FUdR)は関東化学から購入した。
データは平均±標準誤差として表した。統計学的な比較は、一元配置分散分析(ANOVA)とダンカンの多重範囲検定により行った。C.エレガンスの寿命については、カプラン−マイヤー生存曲線およびログランク検定を用いて平均生存時間(MST)を分析した。統計解析はSPSS(バージョン16.0)を用いて行い、p値<0.05を有意差ありとした。
プロポリス抽出物(OP)の調製:
プロポリスは、おきなわ養蜂の養蜂場(沖縄県)で採取されたものを用いた。乾燥したプロポリス原塊を、滅菌乳棒と乳鉢を用いて粉末化した。プロポリス粉末1g当たり100%エタノール50mlを用いてプロポリスを抽出した。プロポリス粉末とエタノールの混合物を3時間超音波処理(AS ONE社)し、25°Cで21時間振盪(バイオシェーカーBR-300LF、タイテック社)した。懸濁液を、Whatman(登録商標)セルロース濾紙を用いて濾過し、濾液を5分間、14357×gで数回遠心分離に供した。透明な上清を減圧濃縮し、黄色で乾燥したプロポリスの抽出物(320g、収率32%)を得た。この抽出物250mgを100%エタノール1mLに溶解し、プロポリスの25%チンキ剤を調製した。このサンプルを-20℃で保存した。サンプルは、適切な最終濃度となるようにジメチルスルホキシド(DMSO)またはエタノール中に希釈した。
PAK1阻害試験:
PAK1阻害活性は、文献(Nguyen, B. C. Q.; Be Tu, P. T.; Tawata, S.; Maruta, H. Combination of immunoprecipitation (IP)-ATP_Glo kinase assay and melanogenesis for the assessment of potent and safe PAK1-blockers in cell culture. Drug Discov. Ther. 2015, 9 (4), 289-295.)記載の"Macaroni-Western"キナーゼアッセイによって測定した。A549細胞(2×10 5細胞/ウェル)を24時間D-MEM培地で前培養し、製造例1で得られたプロポリス抽出物(1.5,10μg/mL)で24時間処理した。次いで、細胞を細胞溶解バッファー(50mM Tris-HCl、pH7.5、150mM NaCl、1%トリトンX-100)500μLに溶解し、30分間氷冷した。細胞溶解物を免疫沈降試験のために、4℃で5分間、100×g で遠心分離し、上清を希釈緩衝液50μl(50mM Tris-HCl、pH7.5、150mM NaCl、100μg/ mL BSA)のみ、または、抗PAK1のIgG(1:50希釈)の存在下で、4℃で1時間インキュベートした。次いでサンプルを、ロータリーミキサー(日伸理化社)を用いて振盪しながら、プロテインAアガロース10μLの存在下、4℃で1時間さらにインキュベートした。遠心分離後、ペレット(PAK1を含む)を洗浄バッファー500μl(50mM Tris-HCl、pH7.5、150mM NaCl)で2回洗浄した。免疫沈降(IP)-PAK1ペレットを、キナーゼバッファー(50mM Tris-HCl、pH7.5、150mM NaCl、20mM MgCl2、0.1mg/mL BSA)35μLに再懸濁した。2μM ATP蒸留水溶液10μL、MBPの基質(蒸留水中1mg/mL)5μLを添加してキナーゼ反応を行った。反応は、一定に攪拌しながら37℃で1時間インキュベートして行った。インキュベーション後、等量のキナーゼGlo試薬(50μL)を各ウェルに添加し、さらにプレートを30分間インキュベートして蛍光シグナルを安定化させた。透明な上清を、96ウェルプレートに移して分析した。各ウェルの発光量を、マイクロプレートリーダーMTP-880Lab(コロナ社)を用いて0.5秒の積分時間で測定した。プロポリス抽出物のPAK1活性は、対照に対する割合として算出した。IC50を表1に示す。グリーンプロポリス、Bio 30についても同様にしてIC50を求めた。
(細胞生存性)
B16F10メラノーマ細胞を、熱不活性化FBS10%及び1%ペニシリン/ストレプトマイシン(各10,000U/mL,100μg/mL)を添加したD-MEM中で、5%CO2を含む37℃加湿雰囲気中で培養した。細胞生存率(または成長速度)は、トリパンブルー色素排除試験法を用いて測定した(Nguyen, B. C. Q.; Be Tu, P. T.; Tawata, S.; Maruta, H. Combination of immunoprecipitation (IP)-ATP_Glo kinase assay and melanogenesis for the assessment of potent and safe PAK1-blockers in cell culture. Drug Discov. Ther. 2015, 9 (4), 289-295.)。すなわち、B16F10細胞(2×104細胞/ウェル)を24ウェルプレートに播種した。24時間前培養した後、各濃度(10、20、0μg/ mL)で製造例1で得られたプロポリス抽出物(OP)により37℃、72時間処理した。次いで、細胞をリン酸バッファーで2回洗浄し、Accutase(登録商標)で回収し、生存(染色されていない)細胞数をトリパンブルー色素排除試験により求めた。細胞生存性をコントロールに対する割合として算出した。結果を図2に示す。
メラニン含有量はYoonらの方法に従って測定した(Yoon, N.Y.; Eom, T-K.; Kim, M-M.; Kim, S-K. Inhibitory effect of Phlorotannins isolated from Ecklonia cava on mushroom tyrosianse activity and melanin formation in mouse B16F10 melanoma cells. J. Agri. Food. Chem. 2009, 57, 4124-4129.)。すなわち、B16F10細胞を2×104細胞/ウェルの密度で24ウェルプレートに播種した。前培養24時間後、培地を標準(10%FBS添加)または無血清培地と交換し、各濃度(5-40μg/ mL)の製造例1で得られたプロポリス抽出物(OP)で処理した。1時間後、PAK1を活性化するイソブチル−1−メチルキサンチン(IBMX;メラニン形成ホルモン)100μMを培地に添加し、細胞を37℃でさらに72時間インキュベートした。細胞をリン酸バッファーで洗浄後、10%DMSOを含む500μLのNaOH(1N)溶液に溶解させた。メラニンの溶解を促進するために、サンプルを1時間80℃でインキュベートした。 混合ホモジネートの490nmにおける光学密度を測定した。メラニン含有量をコントロールに対する割合として算出した。結果を図3に示す。
チロシナーゼ阻害活性は、文献(Gevensleben, H.; Gohring, U.-J.; Buttner, R.; Heukamp, L. C.; Kunz, G.; Dimpfl, T.; Jackisch, C.; Ortmann, O.; Albert, U.-S.; Bender, R.; et al. Comparison of MammaPrint and TargetPrint results with clinical parameters in German patients with early stage breast cancer. Int. J. Mol. Med. 2010, 26 (6), 837-843.)記載の方法を若干改変して測定した。B16F10細胞を2×104細胞/ウェルの密度で24ウェルプレートに播種した。24時間前培養後、培養培地は、各濃度(10-40μg/mL)の製造例1で得られたプロポリス抽出物を添加した標準(10%FBS含有)及び無血清培地で置換した。1時間後、IBMX(100μM)を添加し、さらに72時間37℃でインキュベートした。次いで、細胞を氷冷リン酸バッファーで洗浄し、1%トリトンX-100を含むリン酸バッファー(pH 6.8)で溶解した(500μL/ウェル)。プレートを-80℃で30分間凍結した。1%L-DOPAの100μLを解凍、混合した後、各ウェルに添加した。37℃で2時間インキュベーション後、490nmにおける吸光度を測定した。チロシナーゼ阻害活性をコントロールに対する割合として求めた。結果を図4に示す。
寿命延長試験:
同期させたC.エレガンスの卵(60〜100個)を、E.coli(OP50)を含み、製造例1で得られたプロポリス抽出物(1μg/mL)又はレスベラトロール(10μg/ml)を添加した新鮮なNGM寒天培地上に置いた。成虫期(3日目)に入った後、繁殖を阻害するためにFUdR 400μL(0.5mg/ mL)を寒天培地に添加した。成虫には、2日ごとにOP50を与えた。生存線虫の数は、毎日計数した(Yanase, S. PAK1-deficiency/down-regulation reduces brood size, activates HSP16.2 gene and extends lifespan in Caenorhabditis elegans. Drug Discov. Ther. 2013, 7 (1), 29-35.Upadhyay, A.; Chompoo, J.; Taira, N.; Fukuta, M.; Tawata, S. Significant Longevity-Extending Effects of Alpinia zerumbet Leaf Extract on the Life Span of Caenorhabditis elegans. Biosci Biotechnol Biochem 2013, 77 (2), 217-223.)。結果を図5に示す。(A)は生存曲線、(B)は生存日数の中央値である。
HSP16.2発現誘導試験:
組換えHSP-16.2-GFP融合遺伝子(HSP-16.2::GFP)を有するC.エレガンスCL2070株を用いた(Yanase, S. PAK1-deficiency/down-regulation reduces brood size, activates HSP16.2 gene and extends lifespan in Caenorhabditis elegans. Drug Discov. Ther. 2013, 7 (1), 29-35.)。線虫をNGM寒天培地中で大腸菌(OP50)を与えて20℃で増殖させた。各群約30匹の成虫を、製造例1で得られたプロポリス抽出物(0.5,1,5μg/ mL)を添加した新しいNGM寒天培地に移し、20℃で48時間インキュベートした。線虫に35℃で2時間熱ショックを与えた後、20℃で4時間インキュベートし回復させた。各群の線虫は、顕微鏡観察のために0.5Mアジ化ナトリウムの滴(1μL)で固定した。GFPトランスジェニック線虫の写真をKEYENCE BZ-X700蛍光顕微鏡を用いて撮影し、蛍光を測定した。蛍光強度はコントロールに対する割合として算出した。結果を図6に示す。
Claims (2)
- ニムフェオール−A、ニムフェオール−B及びニムフェオール−Cから選ばれる少なくとも1種のフラバノン化合物を含むプロポリスを含有するp21活性化キナーゼ阻害剤を有効成分として含有するアルツハイマー病の予防・治療剤。
- ニムフェオール−A、ニムフェオール−B及びニムフェオール−Cから選ばれる少なくとも1種のフラバノン化合物を含むプロポリスを含有するp21活性化キナーゼ阻害剤を有効成分として含有する抗熱ストレス剤。
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