JP2018515095A - ミトコンドリア分裂調節剤のスクリーニング方法 - Google Patents
ミトコンドリア分裂調節剤のスクリーニング方法 Download PDFInfo
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Abstract
Description
本発明の他の目的は、前記PPD類ジンセノサイド化合物を含むミトコンドリア分裂調節剤のスクリーニング組成物を提供することにある。
がん細胞に対してプロトパナキサジオール(protopanaxadiol、PPD)類ジンセノサイド化合物が細胞毒性を示すかどうかを確認しようとした。
実施例2:ドキソルビシンの抗がん活性に及ぼすPPDの影響
ミトコンドリア媒介性抗がん活性を示すと知られている抗がん剤の一種であるドキソルビシンの抗がん活性に及ぼすPPD類ジンセノサイド化合物の効果を研究した。
ヒト乳がん細胞株MCF−7細胞、前記実施例1で優秀な抗がん活性を示すと確認されたC−KまたはPPD、ホルモン受容体の拮抗剤として作用してホルモン媒介性がんの成長を阻害する抗がん活性を示すタモキシフェン、及びミトコンドリア媒介性抗がん活性を示すと知られている抗がん剤の一種であるドキソルビシンを使用して、抗がん剤に対するがん細胞の感受性に及ぼすPPD類ジンセノサイド化合物の効果を確認しようとした。
MCF−7細胞に10μg/mlのC−KまたはPPDを含む培地を加えて12時間培養した後、10μg/mlのC−KまたはPPDと0または5μg/mlのドキソルビシンとを含む培地に交替して24時間培養した。培養が終了された細胞を破砕して、これを対象にリン酸化JNKに対する抗体、PARPに対する抗体、切断されたPARPに対する抗体、カスパーゼ−9に対する抗体または切断されたカスパーゼ−9に対する抗体を使用したウェスタンブロット分析を行った(図3a)。この時、陰性対照群としてはジンセノサイドを処理しない実験群を使用し、陽性対照群としてはドキソルビシンに対して特別な効果を示さないことが確認されたPPD類ジンセノサイド化合物であるF2を処理した実験群を使用した。
前記実施例2の結果から、PPD類ジンセノサイド化合物に属するC−KまたはPPDがミトコンドリア媒介性抗がん活性を示すと知られている抗がん剤の一種であるドキソルビシンの抗がん活性を促進されることを確認したため、前記C−KまたはPPDがミトコンドリアに影響を及ぼすかどうかを確認しようとした。
MCF−7細胞に10μg/mlのC−KまたはPPDを含む培地を加えて24時間培養した後、5μg/mlのドキソルビシンを含む培地に交替して0または4時間培養した。培養が終了した細胞に4%パラホルムアルデヒドを加えて固定し、0.5%Triton(登録商標)X−100溶液を加えて穿孔した後、シトクロム−Cに対する抗体を使用して30分間免疫染色した。染色が終了した後、前記細胞をPBSで洗浄し、蛍光ラベルされた2次抗体を30分間加えて反応させて、PBSで洗浄した後、共焦点顕微鏡で撮影し、発色された蛍光水準を測定した(図4a)。この時、陰性対照群としてはジンセノサイドを処理しない実験群を使用し、陽性対照群としてはドキソルビシンに対して特別な効果を示さないことが確認されたPPD類ジンセノサイド化合物であるF2を処理した実験群を使用した。
実施例3−2:ミトコンドリアの損傷誘導に及ぼす効果
前記実施例3−1の結果からC−KまたはPPDがドキソルビシンによりミトコンドリアでシトクロム−Cの放出を促進させることを確認したため、前記C−KまたはPPDがミトコンドリアを損傷させることができるかどうかを確認しようとした。
前記実施例3−2の結果からC−KまたはPPDはミトコンドリアの損傷を誘発させることを確認したので、ミトコンドリア融合に関与するタンパク質(Mfn1またはMfn2)の発現を抑制させて、ミトコンドリアの分裂を誘発し、これにドキソルビシンを処理してミトコンドリアの分裂とドキソルビシンの抗がん活性の関連性を分析しようとした。
対照群:5’−CCUACGCCAAUUUCGU−3’−dTdT(配列番号1)
Mfn1:5’−GUGUAGAUUCUGGUAAUGA−3’−dTdT(配列番号2)
Mfn2:5’−CGAUGCAACUCUAUCGUCA−3’−dTdT(配列番号3)
前記合成された各siRNAをMCF−7細胞に導入し、12時間培養して、前記細胞をsiRNAが含まれない正常培地で48時間再び培養した後、これらの細胞で発現されるミトコンドリア融合に関与するタンパク質(Mfn1またはMfn2)の発現水準をウエスタンブロット分析によって確認した(図6a)。
Claims (7)
- (a)分離された細胞にプロトパナキサジオール(protopanaxadiol、PPD)類ジンセノサイド化合物とミトコンドリアの分裂を調節することができると予想される候補化合物を処理する候補化合物処理段階;
(b)前記候補化合物を処理した細胞内ミトコンドリアの分裂水準を測定する段階;及び
(c)前記候補化合物を処理しない陰性対照群と比較して、前記ミトコンドリアの分裂水準を促進または抑制する候補化合物を選別する段階を含む、ミトコンドリア分裂調節剤のスクリーニング方法。 - 前記分離された細胞が、インスリン分泌細胞またはがん細胞である、請求項1に記載の方法。
- 前記PPD類ジンセノサイド化合物が、下記化学式(1)のPPD(protopanaxadiol)である、請求項1に記載の方法。
- 前記PPD類ジンセノサイド化合物が、下記化学式(2)のコンパウンド−K(compound−K、C−K)である、請求項1に記載の方法。
- プロトパナキサジオール(protopanaxadiol、PPD)類ジンセノサイド化合物を含む、ミトコンドリア分裂調節剤のスクリーニング用組成物。
- 前記PPD類ジンセノサイド化合物が、PPD(protopanaxadiol)またはコンパウンド−K(compound−K、C−K)である、請求項5に記載の組成物。
- 請求項5または請求項6に記載の組成物を含む、ミトコンドリア分裂調節剤のスクリーニング用キット。
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KR1020150071480A KR101751392B1 (ko) | 2015-05-22 | 2015-05-22 | 미토콘드리아 분열 조절제의 스크리닝 방법 |
KR10-2015-0071480 | 2015-05-22 | ||
PCT/KR2015/006825 WO2016190480A1 (ko) | 2015-05-22 | 2015-07-02 | 미토콘드리아 분열 조절제의 스크리닝 방법 |
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US (1) | US10398710B2 (ja) |
EP (1) | EP3299813A4 (ja) |
JP (1) | JP6535107B2 (ja) |
KR (1) | KR101751392B1 (ja) |
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JP2021512874A (ja) * | 2018-02-02 | 2021-05-20 | パイアン バイオテクノロジ− インコーポレイテッド | 単離ミトコンドリアを含む関節リウマチの予防または治療のための医薬組成物 |
KR102292141B1 (ko) * | 2020-02-27 | 2021-08-23 | 가톨릭대학교 산학협력단 | 근육긴장저하 관련 질환의 예방 또는 치료용 약물의 스크리닝 방법 및 근육긴장저하의 진단을 위한 정보 제공 방법 |
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JP2007228855A (ja) * | 2006-02-28 | 2007-09-13 | Univ Of Tokushima | 抗肥満剤のスクリーニング方法 |
US20130337453A1 (en) * | 2010-10-21 | 2013-12-19 | Tufts University | Extracellular mitochondria-based screening and treatment |
US20140274904A1 (en) * | 2011-05-13 | 2014-09-18 | The Board Of Trustees Of The Leland Stanford Junior University | Inhibitors of mitochondrial fission and methods of use thereof |
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KR20020042020A (ko) | 2000-11-29 | 2002-06-05 | 정해영 | 디하이드록시벤즈알데하이드 또는 이의 유도체를유효성분으로 하는 미토콘드리아 보호제 및 항노화제 |
CN1623554A (zh) * | 2003-12-06 | 2005-06-08 | 山东绿叶天然药物研究开发有限公司 | 一种以c-k为有效成分的抗癌辅助药物及其应用 |
US20050245465A1 (en) * | 2004-04-28 | 2005-11-03 | Tae-Wan Kim | Compounds for treating Alzheimer's disease and for inhibiting beta-amyloid peptitde production |
MX2008014525A (es) * | 2006-05-17 | 2008-11-27 | Bayer Consumer Care Ag | Uso de ginsenosidos y extractos que los contienen. |
KR20110079564A (ko) | 2009-12-31 | 2011-07-07 | (주)아모레퍼시픽 | 인삼 열매 추출물을 함유하는 미토콘드리아 활성화를 위한 조성물 |
CN102391345B (zh) * | 2011-10-25 | 2012-10-31 | 吉林大学 | 一种拟人参皂苷-Rh2及在制备治疗肿瘤药物的应用 |
JP2013142070A (ja) * | 2012-01-11 | 2013-07-22 | Nihon Univ | ミトコンドリア分裂阻害剤を用いたtrail抵抗性の克服 |
KR101384642B1 (ko) | 2012-06-22 | 2014-04-22 | 이화여자대학교 산학협력단 | N―말단이 제거된 유비퀴틴 c―말단 가수분해효소―l1(nt―uch―l1)를 유효성분으로 포함하는 파킨슨병 예방 및 치료용 약학적 조성물 |
US20150168379A1 (en) * | 2013-12-12 | 2015-06-18 | Macau University Of Science And Technology | Method of identifying and screening drug candidate for preventing and/or treating ischemic myocardial disease |
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JP2007228855A (ja) * | 2006-02-28 | 2007-09-13 | Univ Of Tokushima | 抗肥満剤のスクリーニング方法 |
US20130337453A1 (en) * | 2010-10-21 | 2013-12-19 | Tufts University | Extracellular mitochondria-based screening and treatment |
US20140274904A1 (en) * | 2011-05-13 | 2014-09-18 | The Board Of Trustees Of The Leland Stanford Junior University | Inhibitors of mitochondrial fission and methods of use thereof |
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DONG, G. ET AL.: "Rg1 prevents myocardial hypoxia/reoxygenation injury by regulating mitochondrial dynamics imbalance", MITOCHONDRION, vol. Vol.26, JPN6018037187, 24 November 2015 (2015-11-24), pages 7 - 18, XP029414020, DOI: doi:10.1016/j.mito.2015.11.003 * |
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KR20160137809A (ko) | 2016-12-01 |
KR101751392B1 (ko) | 2017-06-29 |
US10398710B2 (en) | 2019-09-03 |
JP6535107B2 (ja) | 2019-06-26 |
CN107912056A (zh) | 2018-04-13 |
WO2016190480A1 (ko) | 2016-12-01 |
US20180125864A1 (en) | 2018-05-10 |
EP3299813A1 (en) | 2018-03-28 |
CN107912056B (zh) | 2019-10-08 |
EP3299813A4 (en) | 2019-02-20 |
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