JP2011510976A - イノシトール1,4,5−三リン酸受容体サブタイプ3の阻害用の組成物 - Google Patents
イノシトール1,4,5−三リン酸受容体サブタイプ3の阻害用の組成物 Download PDFInfo
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Abstract
本発明は、カフェインおよび/またはその類似体、および/またはこれらの薬学的に許容可能な塩を有効成分として含む、イノシトール1,4,5−三リン酸受容体(IP3R)サブタイプ3(IP3R3)を阻害するための薬剤が提供される。受容体を通じたCa2+放出と関連する疾病の予防用および/または治療用の組成物も提供される。
Description
本出願は、2008年1月31日付で出願された韓国特許出願第10−2008−0010156号の優先権利益を主張し、前記韓国特許出願の明細書は、本明細書に参照として含まれる。
膠芽細胞腫細胞株は、10%ウシ胎児血清(FBS)、1%L−グルタミン、1%ピルビン酸ナトリウム、ペニシリン(50単位/mL)およびストレプトマイシン(50単位/mL)が補充されたDulbecco's変形Eagle's培地(DMEM;Gibco、Invitrogen、USA)に保持した。ヒト膠芽細胞腫は、20%FBS、1%L−グルタミン、1%ピルビン酸ナトリウム、ペニシリン(50単位/mL)、およびストレプトマイシン(50単位/mL)が補充されたDMEMに保持し、使用時まで保管した。
カフェインの多様なGBM細胞株に対する運動性、浸潤性および増殖性の阻害活性を試験した。
まず、運動性に対する効果を試験するために、神経膠腫細胞株としてU178MG、U87MG、wtEGFR、およびΔEGRF細胞を使用した。前記細胞株は、それぞれEmory Uni(U178MG)、及びATCC(U87MG、T98G、およびM59K)から入手した。すべての細胞株を、12−ウェル培養プレート内の血清含有培地(Emory Uni製)で単層増殖させた。10μLピペットチップで掻爬(scrape)を作り、10mMカフェイン、1μMタプシガルギン、または10μMリアノジンをそれぞれ添加後、プレートをインキュベータに戻して培養した(各細胞株当りn=3乃至4、37℃)。増殖を防止するために、フルオロデオキシウリジン (FdU/U;Sigma社製)を添加した。24時間培養後、細胞を4%パラホルムアルデヒドで固定した。損傷領域内の3個の10×フィールドの再増殖の広さを測定し、損傷領域の傷の縫合の平均パーセントを測定した。カフェイン処理していない細胞株を対照群として使用した。
**p<0.01、事後のニューマン−クールズ分散分析(ANOVA with Newman−Keuls post hoc.)
浸潤の阻害効果を試験するために、膠芽腫細胞として、U178MG、U87MG、U373MG、およびT98Gを使用した。前記細胞株らはそれぞれATCC(アメリカ培養細胞系統保存機関)から得た。前記細胞らにカフェインをそれぞれ1、2、5、および10mMを添加した(n=4)。24−ウェルプレートで、8μm孔径(Corning社、NY、米国)を含むトランスウェルインサートを使用して細胞浸潤を検定した。浸潤試験用に、インサートを2mg/ml基底膜マトリゲル(BD Bioscience社、Bedford、MA、米国)でコーティングした。無血清培地(FBS、DMEM、GIBCO社より、Invitrogen社、米国)内の1×105細胞をインサート上段面にプレーティングし、完全培地をチャンバー下部に入れて化学誘引物質として作用するようにした。37℃で24時間培養後、インサート上段面上の細胞を綿棒で拭いて除去し、メンブレンの下段面へ遊走した細胞をDAPI(Molecular Probes、Invitrogen社、米国)で染色し、倍率40倍で、顕微鏡で無作為撮影した。カフェイン未処理細胞(対照群)の平均数を100%浸潤と見なした。
カフェインの増殖能における阻害効果を試験するために、軟寒天試験を行った。1×104個の細胞を、6−ウェルプレート中の、0.6%ベース寒天を覆った軟寒天(0.3%、Difco社)に接種した。凝固した細胞層を、0.5、1、2、5、および10mMのカフェインを含有する培地で覆い、前記培地は4日毎に交換した。コロニーが発生するように、前記細胞を37℃で14乃至17日間培養した。その後、コロニーを0.05%クレシルバイオレットで染色して撮影した。対照群として、カフェイン処理していないものを使用した。各試験はn=3で行った。
U178MG細胞を10mMカフェインで処理した。100秒の処理後、細胞を2つの群に分けた後、GPCR(G−protein coupled receptors)アゴニスト、すなわち100ng/ml EGFまたは10μMブラジキニンでそれぞれ処理した。細胞内電流を測定して、EGFまたはブラジキニンで刺激されたU178MGでのカフェインによる細胞内Ca2+放出の遮断を試験した。細胞内電流測定を通じたカルシウムイオン濃度測定は「C.Justin Lee,et al.,The Journal of Physiology,Astrocytic control of synaptic NMDA receptor,2007」(前記文献は参照として本明細書に含まれる)の記載通りに行った。カフェインを処理していない群を対照として使用した。前記で得られた結果を図4a(EGF)および図4b(ブラジキニン)にそれぞれ示した。前記図4aおよび図4bに示したように、カフェインを処理した群では、アゴニストを処理しても、[Ca2+]iが大きく増加していないことが分かる。
4.1.mRNA発現の測定
ヒト神経膠腫細胞株(U87MG、U178MG、U373MG、T98G、M059K)、ヒト膠芽細胞腫細胞株(SH−SY5Y)、およびHEK293T細胞株での、IP3Rsおよびグリセルアルデヒド‐3‐ホスファターゼ(GAPDH)のmRNA発現を測定した。mRNAの発現はRT−PCR(逆転写−ポリメラーゼ連鎖反応)で測定した。Trizol試薬(Invitrogen社、Carlsbad、CA)と共に上記の調製サンプルから全RNAを分離し、1μgの分離されたRNAを増幅させた。各サイクルは、94℃で30秒間の変性、55℃で30秒間のアニーリング、および72℃で60秒間の伸張で構成された。使用されたプライマー配列は次の通りである:
IP3R1センス:5'−CTCTGATCGTTTACCTG−3'(配列番号1)、
ITPR1アンチセンス:5'−TCTTCTGCTTCTCACTCCTC−3'(配列番号2);
IP3R2センス:5'−AGAAGGAGTTTGGAGAGGAC−3'(配列番号3)、
IP3R2アンチセンス:5'−TCACCACCTTTCACTTGACT−3'(配列番号4);
IP3R3センス:5'−CTGTTCAACGTCATCAAGAG−3'(配列番号5)、
IP3R3アンチセンス:5'−CATCAACAGAGTGTCACAGG−3'(配列番号6);
GAPDHセンス:5'−AGCTGAACGGGAAGCTCACT−3'(配列番号7)、
GAPDHアンチセンス:5'−TGCTGTAGCCAAATTCGTTG−3'(配列番号8)。
HEK293T細胞をIP3R1(ウシ)およびIP3R3(ウシ)でそれぞれ形質転換した(GFPとIP3R遺伝子を同時に形質転換させたHEK293T細胞はATCCから入手し、かつGFPが入った細胞らのみをCa2+イメージングし、Ca2+イメージングは形質転換させてから2日後に行った)。細胞はその後10mMカフェインで処理した。カフェイン処理した細胞に対して、TFLLR誘導性Ca2+放出(30μM TFLLRで処理)に対する遮断度を評価した。結果を図6aおよび図6bに示す。図6aにおいて、IP3R1が発現する場合には、TFLLR誘導性Ca2+放出に対するカフェインによる遮断は顕著でなかった。しかしながら、図6bに示されているように、IP3R3を発現する場合には、TFLLR誘導性Ca2+放出に対するカフェインによる遮断が観測された。
海馬の器官型切片培養(Organotypic hippocampal slice cultures、OHSCs)において、カフェインがU178MG神経膠腫細胞の浸潤を減少させるかどうかについて試験した。前記OHSCsは「Simoni AD and YuLM,Preparation of organotypic hippocampal slice cultures:interface method.Nat Protoc.2006;1(3):1439〜45」の記載に従って調製した。器官型神経膠腫浸潤を若干変更した(Eyupoglu IY、Hahnen E、Buslei R、Siebzehnrubl FA、Savaskan NE、Luders M、Trankle C、Wick W、Weller M、Fahlbusch R、Blumcke I.Suberoylanilide hydroxamic acid(SAHA)has potent anti−glioma properties in vitro、ex vivo and in vivo.J Neurochem.2005 May;93(4):992〜9)。簡略に説明すれば、0、1、2、5、および10mMのカフェインの存在下で、DiI株化(DiI−strained)U178MG細胞(5000細胞/20nl)を6日目の海馬器官型切片上に乗せた。1時間および120時間経過後、前記神経膠腫細胞の挙動を、倒立型共焦点レーザー走査顕微鏡(inverted confocal laser scanning microscope)(Zeiss LSM5、Carl Zeiss社、ドイツ)を使用して観察した。得られた結果を図7aに示す。図7aは、6日目の切片表面に乗せたU178MG細胞を示す写真で、Adobe Photoshop 7 softwareを利用して1時間後のイメージ(緑色)と120時間後のイメージ(赤色)を重ねておいた併合イメージである。スケールバー:500μm。
体積=(長さ×幅2)/2
各細胞株(U178MG、U87MG、U373MG、およびT98MG)でのカフェイン濃度に依存する細胞生存率を、比色MTT還元アッセイ(colorimetric MTT reduction assay)によって評価した。カフェイン処理前に、細胞を96−ウェルプレートで増殖させた。処理24時間後、MTT溶液(2.5mg/ml)10μlをそれぞれのウェルに入れ、細胞を37℃で4時間培養した。細胞をDMSOで可溶化させ、570nmにおいて分光光度的に定量化した。データは、対照値に対する生存率で表示した。
カフェイン作用はストア感受性チャンネルまたはストア枯渇に依存的であることを示すために、Ca2+添加およびCa2+無添加浴槽(bath)でのカフェイン作用を試験した。
[実施例7]
カフェインのみならず、カフェイン類似体もカフェインと同等程度の活性、つまり、脳腫瘍細胞でのCa2+放出に対する阻害、およびCa2+シグナル伝達による細胞増殖、移動および浸潤阻害活性を有するかどうかを確認するために、いくつかのカフェイン類似体のCa2+放出に対する阻害活性を測定した。
本実施例で使用されたマイクロアレイ解析は次のような方法で行った。
全RNAは、10個の正常ヒト脳組織および27個の神経膠腫から、使用説明書に従ってTRIZOL(登録商標)試薬(Invitrogen社、英国)を用いて単離し、その後RNeasy mini kit(Qiagen社、Valencia、CA)で精製した。
NanoDrop分光光度計(NanoDrop Technologies社、Wilmington、Delaware、米国)を用いて、OD260/280を測定し、全RNA量および純度を測定した。A260/280比率が>1.8であるものを、マイクロアレイ実験に使用可能なものと見なした。RNAの長さ分布および完全性は、Agilent Total RNA Nano chip assay(Agilent Technologies社、Palo Alto、CA)を用いる蛍光検出(Agilent Bioanalyzer 2100)によるキャピラリー電気泳動で、28Sおよび18S rRNAバンドの存在に対して評価した。理論上、28Sバンドの強度は、18Sバンドの強度の2倍にならなければならない。
遺伝子発現解析は、Agilent Human 1A(V2)oligo microarry Kit(Agilent Technologies社、PaloAlto、CA)を用いて行った。マイクロアレイは各プローブ当り4個の複製配列(replicate)がアレイを横切って分布するように、つまり、4×20K Multiplexスライドフォーマットで設計した。4個の複製配列は、対照スポット(control spot)を含む、それぞれ20,000個以上の60塩基長のヒト遺伝子及び転写配列を含む。
オリゴマイクロアレイ解析に使用するための蛍光ラベル化cDNAは、アミノアルキル−UTP存在下でAmino allyl MessageAmpTM aRNA kit(Ambion Inc.,Texas)を使用して全RNAを増幅させた後、Cy3またはCy5染料(1色使用の場合はCy3染料)(AmershamPharmacia社、Uppsala、スウェーデン)を結合させて調製した。Agilent 60merオリゴマイクロアレイプロセシングプロトコルを使用して、回転ハイブリダイゼーション化オーブンで、65℃で17時間ハイブリダイゼーションを行った。プロトコルに従ってスライドを洗浄した後、GenePix 4000B アレイスキャナ(Axon Instruments社、Union City、CA)でスキャンした。
スキャンされたイメージは、GenePix Pro 6.0 software(Axon Instruments社、Union City、CA)を用いて解析して、遺伝子発現比率を得た。変換されたデータはLOWESS回帰式[Cell Mol Life Sci.2007 Feb;64(4):458〜78]を用いて正常化し、その後GeneSpring GX 7.3ソフトウェアプログラム(Agilent Technologies Inc.米国)を用いて解析した。1色デフォルト正常化(チップあたり:平均または百分位数に正常化させる;遺伝子当たり:平均に正常化させる)と共に、GeneSpring GXは先ずそれぞれの実測強度値をチップの平均値で割った。その後、各値を、サンプルにわたる各遺伝子の平均値でさらに割って、最終正常化値を得た。
Claims (4)
- カフェイン、7−イソプロピルテオフィリン、7−(β−ヒドロキシエチル)テオフィリン、キサンチン、テオフィリン、1,7−ジメチル−3−イソブチルキサンチンおよびこれらの薬学的に許容可能な塩からなる群より選択される1種以上を有効成分として含む、イノシトール1,4,5−三リン酸受容体サブタイプ3(IP3R3)の阻害用の組成物。
- カフェイン、7−イソプロピルテオフィリン、7−(β−ヒドロキシエチル)テオフィリン、キサンチン、テオフィリン、1,7−ジメチル−3−イソブチルキサンチンおよびこれらの薬学的に許容可能な塩からなる群より選択される1種以上を有効成分として含む、Ca2+過剰放出と関連する疾病の予防用または治療用の組成物。
- 前記Ca2+過剰放出と関連する疾病は、脳卒中、不安症、過敏性膀胱炎、炎症性腸疾患、過敏性大腸症候群、てんかん性大膓炎、頭部外傷、偏頭痛、慢性、神経病症性または急性痛症、薬品またはアルコール中毒、神経病性障害、精神病、睡眠障害、恐怖症、強迫観念、外傷後ストレス障害、憂鬱症、てんかん、糖尿病、癌、男性不妊、高血圧、肺高血圧、心臓性不整脈、鬱血性心不全症、狭心症、多嚢胞性腎疾患、デュシェンヌ型筋ジストロフィーからなる群より選択される1種以上の疾病である、請求項2に記載の組成物。
- 請求項1乃至請求項3のうちのいずれか1項に記載の組成物を含む、Ca2+過剰放出と関連する疾病の改善用の食品組成物。
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KR1020080010156A KR20090084150A (ko) | 2008-01-31 | 2008-01-31 | 이노시톨 1,4,5-트리포스페이트 수용체 서브타입 3 억제용조성물 |
PCT/KR2008/000603 WO2009096616A1 (en) | 2008-01-31 | 2008-01-31 | Composition for inhibiting the activity of inositol 1,4,5-triphosphate receptor subtype iii |
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WO2015127455A1 (en) * | 2014-02-24 | 2015-08-27 | Arizona Board Of Regents On Behalf Of Arizona State University | Gene expression based biomarker system for irritable bowel syndrome (ibs) diagnosis |
CN109912598B (zh) * | 2019-03-27 | 2022-09-13 | 四川大学华西医院 | 防治炎症反应的核苷类衍生物及其应用 |
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US5981536A (en) * | 1996-07-31 | 1999-11-09 | Hoechst Aktiengesellschaft | Use of xanthine derivatives for the modulation of apoptosis |
US6165516A (en) * | 1996-11-27 | 2000-12-26 | Wm. Wrigley Jr. Company | Method of controlling release of caffeine in chewing gum |
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JPN6013000546; Biochem. J. vol.300, 1994, p.81-84 * |
JPN6013000547; Journal of Physiology vol.433, 1991, p.229-240 * |
JPN6013026640; JAPIC 日本の医薬品 構造式集 2005 , 2005, p.28 * |
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WO2018124236A1 (ja) * | 2016-12-27 | 2018-07-05 | 国立大学法人大阪大学 | 難治性心疾患治療用医薬組成物 |
JPWO2018124236A1 (ja) * | 2016-12-27 | 2019-11-14 | 国立大学法人大阪大学 | 難治性心疾患治療用医薬組成物 |
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US20110039869A1 (en) | 2011-02-17 |
US20130143904A1 (en) | 2013-06-06 |
KR20090084150A (ko) | 2009-08-05 |
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