JP2016522162A - p34の発現抑制剤または活性抑制剤を有効成分で含む癌の治療または転移抑制用組成物 - Google Patents
p34の発現抑制剤または活性抑制剤を有効成分で含む癌の治療または転移抑制用組成物 Download PDFInfo
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Abstract
Description
本発明は、p34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤を有効成分で含む癌の予防または治療用組成物を提供することを目的とする。
1)p34タンパク質の発現細胞株に被検物質を処理する段階;
2)前記細胞株でp34遺伝子の発現程度またはp34タンパク質の活性程度を測定する段階;及び
3)前記p34遺伝子の発現程度またはp34タンパク質の活性程度が被検物質を処理しない対照群に比べて減少した被検物質を選別する段階。
1)生物学的試料にNEDD4−1(Neuronal precursor cell−expressed developmentally down−regulated 4−1)の発現抑制剤または活性抑制剤を処理する段階;及び
2)前記生物学的試料で癌細胞の増殖可否を測定する段階。
発明の効果
1−1.内因性p34及びNEDD4−1の間の相互作用の分析
(1)NEDD4−1に相互作用するタンパク質を同定するため、細胞溶解液からNEDD4−1タンパク質に対する抗体を利用して免疫沈降法、タンデム親和性精製及び質量分析を実行した。まず、免疫沈降法を実行するために、293(HEK293)細胞、前立腺癌細胞であるDU145及び乳房癌細胞であるMCF7の溶解液を抗−NEDD4−1抗体と各々混合した後、4℃で12時間の間培養した。その後、20μlのタンパク質A/G Plus−Sepharose beads(Santa Cruz Biotechnology、Santa Cruz、CA、USA)を前記培養物に加えて混合した後、2時間の間追加培養した。収得された免疫沈降物を溶解緩衝液(nonidet P−40 lysis buffer)で5回洗浄した後、20μlの2xSDSサンプル緩衝液を処理し加熱した。
外因性に発現されるp34とNEDD4−1の間の相互作用を調査するために、内因性ではp34を発現しない293細胞をGFP−tagged p34及び/またはmyc−tagged NEDD4−1を発現する構造物(construct)でトランスフェクションさせた。以後、293細胞の溶解物を免疫ブロットを通じて分析した。その結果を図6に示した。
p34とNEDD4−1、PTENの間の相互作用を観察するために、下記のようにGSTプルダウン分析(GST Pull−down analysis)を実行した。まず、E.coli BL−21(DE3)株から発現されて精製された500ngのGST−p34タンパク質またはGSTタンパク質(対照群)を準備した後、これをNEDD4−1が欠失された変異細胞株と反応緩衝液(20mM Tris−HCl pH7.5、120mM NaCl)で混合した後、30℃で1時間の間培養した。次に、GSTプルダウン緩衝液(20mM Tris−HCl pH8.0、500mM NaCl、1% Triton X−100、0.02% BSA、5mMメルカプトエタノール)を加えて反応を停止させた。その後、GST及び関連タンパク質をグルタチオン−セファロースビーズを利用して4℃で1時間の間プルダウンさせた。タンパク質複合体をGSTプルダウン緩衝液で6回洗浄して2x SDSサンプル緩衝液を加えた。免疫沈降物内のp34及びNEDD4−1の存在は、抗−GST、抗―T7抗体を利用した免疫ブロットを通じて各々分析した。その結果を図7及び図8に示した。
(1)前記実施例1−3を通じて、p34と相互作用すると確認されたNEDD4−1タンパク質のドメインを分析した。このために、NEDD4−1 cDNAを発現するプラスミドからT7−taggedベクターを利用してT7−tagged野生型(wild−type)NEDD4−1とNEDD4−1の一部ドメインが欠失されたNEDD4−1変異体を製造した。精製されたGST−p34タンパク質を、T7−tagged野生型NEDD4−1またはNEDD4−1変異体(C2、WWs及びHECT(homologous to the E6−AP carboxyl terminus)ドメイン欠失(N1)、WWs及びHECTドメイン欠失(N2)、C2、WW3、WW4及びHECTドメイン欠失(N3)、C2、WW1、WW2及びHECTドメイン欠失(N4)、C2及びWWsドメイン欠失(N5))を発現する293細胞の溶解液と一緒に培養した。以後、GSTプルダウンアッセイを通じてp34が結合するNEDD4−1のドメインを分析した。その結果を図9に示した。
p34がPTENとNEDD4−1の結合に影響を及ぼすか否かを調査するために、GST−PTEN融合タンパク質をMyc−NEDD4−1及びHis−p34を発現する細胞の融解液と培養した後、GSTプルダウンアッセイを実行した。対照群としては、GSTタンパク質を利用した。その結果を図11に示した。
(1)NEDD4−1が細胞内で自己ユビキチン化(auto−ubiquitination)されると以前から報告されたので、p34がNEDD4−1の自己ユビキチン化に及ぶ影響を分析した。293細胞をNEDD4−1及び/またはp34でトランスフェクションした後、前記細胞にMG132(25mM)を処理し、6時間の間培養した。細胞培養物を収得してその抗−Myc免疫沈降物を分析した。その結果を図12に示した。
(1) p34のsiRNAを使用して、p34の発現抑制による沈黙効果を分析した(p34−siRNA:I:5'−GCAAGG GUCUGAAGCGGAA−3、II:5'−GGAAACGGGAGGAGGAGGA−3'、III:5'−CCGAAUUGGACUACCUCAU−3')。MDA−MB−231及びMCF7細胞をp34−siRNAでトランスフェクションした後、各タンパク質の発現程度をウエスタンブロットを通じて分析した。その結果を図16に示した。
(1)最近、NEDD4−1がPTENの試験管内及び細胞内のポリユビキチン化だけではなく、モノユビキチン化を媒介し、PTENのモノユビキチン化は、PTENの核膜孔を通じた核移動(nuclear import)を媒介することで報告された(Wang et al., 2007)。前記実施例2に示したように、p34は、NEDD4−1を通じてPTENポリユビキチン化を調節することを確認した。前記結果に基づいて、本発明者らは、p34がPTENのモノユビキチン化に影響を及ぼすか否かを分析した。
前記実施例1〜実施例3の実験結果を通じて、p34は、NEDD4−1の自己ビクキチン化を阻害することでNEDD4−1タンパク質の安定性を陽性的に調節するので、p34のノックダウンは、PTENポリユビキチン化を減少させて、NEDD4−1により媒介されるPTENのモノユビキチン化を通じてPTENタンパク質水準を増加させることを確認した。
(1)p34の発現がNEDD4−1の原腫瘍性に影響を及ぼすか否かを確認するために、前記実施例4−(3)で確立したテトラサイクリンに誘導が可能であり、p34 shRNAを安定的に発現してp34の発現を枯らしたDU145変異株及びMDA−MB−231変異株を利用し、下記のように実験を実行した。確立された各細胞をBalb/cヌードマウスの皮下に注入して異種移植片(xenograft)腫瘍を形成させた。腫瘍の大きさを3日間隔で2週の間観察し、腫瘍の大きさが180mm3に到逹した時を0日として、10mg/kgの濃度でテトラサイクリンを投与し(対照群はvehicleで水投与)、腫瘍の大きさを続いて観察した。全ての動物実験は、牙山メディカルセンター敷設動物管理及び利用に関する委員会の承認を受けたプロトコルによって進行された。その結果を図47〜図52に示した。
前記実施例1〜実施例5を通じて確認したように、p34活性抑制剤が実際坑癌活性を有するかを検証するための実験を実行した。まず、市販中の化合物ライブラリスクリーニングを通じてp34タンパク質に結合してp34の活性を抑制する化合物を同定した。同定された化合物の化学式を下記に示し、以下では、化合物27(Compound27)で名付けた。
ヒト乳房癌細胞株であるMDA−MB−231と大膓癌細胞株であるLS1034にp34活性抑制剤である化合物27を1μMの濃度で24時間の間処理した後、PTEN抗体を利用して免疫沈降法を実行した。その後、ユビキチン抗体でウエスタンブロットを実行した。その結果を図62に示した。
精製されたNEDD4−1タンパク質、p34タンパク質に反応緩衝液(20mM Tirs−HCl pH7.5、120mM NaCl)及びp34活性抑制剤である化合物27を1mMまたは3mMの濃度で処理し、30℃で1時間反応させた。以後、GSTプルダウン緩衝液(20mM Tirs−HCl pH8.0、500mM NaCl、1% Triton X−100、0.02% BSA、5mMメルカプトエタノール)を使用して反応を停止した後、グルタチオン−セファロースビーズを利用して4℃でプルダウンさせ、抗−His、抗−GST抗体を利用してウエスタンブロットを実行した。その結果を図63に示した。
ヒト乳房癌細胞株であるMDA−MB−231にp34活性抑制剤である化合物27を濃度別に48時間の間処理した後、トリパンブルー染色及びウエスタンブロットを実行した。その結果を図64に示した。
1−1.散剤の製造
p34発現または活性抑制剤 2g
乳糖 1g
前記の成分を混合し気密包に充填して散剤を製造した。
p34の発現または活性抑制剤 100mg
コンスターチ 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
前記の成分を混合した後、通常の錠剤の製造方法によって打錠して錠剤を製造した。
p34発現または活性抑制剤 100g
コンスターチ 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
前記の成分を混合した後、通常のカプセル剤の製造方法によってゼラチンカプセルに充填してカプセル剤を製造した。
2−1.健康食品の製造
p34発現または活性抑制剤 100mg
ビタミン混合物 適量
ビタミンA アセテート 70g
ビタミンE 1.0mg
ビタミンB1 0.13mg
ビタミンB2 0.15mg
ビタミンB6 0.5mg
ビタミンB12 0.2g
ビタミンC 10mg
ビオチン 10g
ニコチン酸アミド 1.7mg
葉酸 50g
パントテン酸カルシウム 0.5mg
無機質混合物 適量
硫酸第一鉄 1.75mg
酸化亜鉛 0.82mg
炭酸マグネシウム 25.3mg
第1リン酸カリウム 15mg
第2リン酸カルシウム 55mg
枸椽酸カリウム 90mg
炭酸カルシウム 100mg
塩化マグネシウム 24.8mg
前記のビタミン及びミネラル混合物の組成比は、比較的健康食品に適合な成分を好ましい実施例で混合組成したが、その配合比を任意に変形実施しても関係なく、通常の健康食品製造方法によって前記の成分を混合した後、顆粒を製造し、通常の方法によって健康食品組成物製造に使用することができる。
Claims (15)
- p34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤を有効成分で含むことを特徴とする癌の予防または治療用薬学的組成物。
- 前記発現抑制剤は、p34遺伝子のmRNAに相補的に結合するアンチセンスヌクレオチド、短ヘアピンRNA(small hairpin RNA:shRNA)、低分子干渉RNA(small interfering RNA:siRNA)及びリボザイム(ribozyme)からなる群より選択された1種以上であることを特徴とする請求項1に記載の癌の予防または治療用薬学的組成物。
- 前記活性抑制剤は、p34タンパク質に特異的に結合する化合物、ペプチド、ペプチド模倣体、気質類似体、アプタマー及び抗体からなる群より選択された1種以上であることを特徴とする請求項1に記載の癌の予防または治療用薬学的組成物。
- 前記p34タンパク質に特異的に結合する化合物は、下記化学式1で表示される化合物またはその薬学的に許容可能な塩であることを特徴とする請求項3に記載の癌の予防または治療用薬学的組成物。
- 前記癌は、口腔癌、肝臓癌、胃癌、結腸癌、乳房癌、肺癌、骨癌、膵膓癌、皮膚癌、頭部癌、頸部癌、子宮頸部癌、卵巣癌、大膓癌、小腸癌、直腸癌、喇叭管癌腫、肛門付近癌、子宮内膜癌腫、膣癌腫、外陰癌腫、ホジキン病(Hodgkin's disease)、食道癌、リンパ腺癌、膀胱癌、胆嚢癌、内分泌腺癌、甲状腺癌、副甲状線癌、副腎癌、軟組織肉腫、尿道癌、陰茎癌、前立腺癌、慢性白血病、急性白血病、リンパ球リンパ種、腎臓癌、輸尿管癌、腎臓細胞癌腫、腎臓骨盤癌腫、中枢神経系腫瘍、1次中枢神経系リンパ種、脊髓腫瘍、脳幹神経膠腫及び脳下垂体腺腫のうち選択された1種以上であることを特徴とする請求項1〜請求項4のうちいずれか1項に記載の癌の予防または治療用薬学的組成物。
- 前記癌は、p34及びNEDD4−1(Neuronal precursor cell−expressed developmentally down−regulated 4−1)を同時に発現する癌であることを特徴とする請求項1〜請求項4のうちいずれか1項に記載の癌の予防または治療用薬学的組成物。
- p34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤を有効成分で含むことを特徴とする癌の予防または改善用食品組成物。
- p34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤を有効成分で含むことを特徴とする癌の転移抑制用薬学的組成物。
- p34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤を個体に投与する段階を含むことを特徴とする癌の治療または転移抑制方法。
- 1)p34タンパク質発現細胞株に被検物質を処理する段階と、
2)前記細胞株でp34遺伝子の発現程度またはp34タンパク質の活性程度を測定する段階と、
3)前記p34遺伝子の発現程度またはp34タンパク質の活性程度が被検物質を処理しない対照群に比べて減少した被検物質を選別する段階と、を含むことを特徴とする癌の治療または転移抑制用候補物質のスクリーニング方法。 - 前記2)段階で遺伝子の発現程度は、RT−PCR(Reverse Transcription Polymerase Chain Reaction)、ノーザンブロット(Northern blot)、cDNAマイクロアレイ混成化反応及びin situ混成化反応からなる群より選択された1種以上の方法で測定することを特徴とする請求項10に記載の癌の治療または転移抑制用候補物質のスクリーニング方法。
- 前記2)段階でタンパク質の活性程度は、免疫沈降法(immunoprecipitation)、放射能免疫分析法(RIA)、酵素免疫分析法(ELISA)、免疫組職化学、ウエスタンブロット(Western Blotting)及びプローサイトメトリー分析法(FACS)からなる群より選択された1種以上の方法で測定することを特徴とする請求項10に記載の癌の治療または転移抑制用候補物質のスクリーニング方法。
- 1)生物学的試料にNEDD4−1(Neuronal precursor cell−expressed developmentally down−regulated 4−1)の発現抑制剤または活性抑制剤を処理する段階と、
2)前記生物学的試料で癌細胞の増殖可否を測定する段階と、を含むことを特徴とするp34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤の癌に対する治療効果予測方法。 - 前記1)段階の生物学的試料は、癌にかかった個体の血液、小便、唾液及び組職からなる群より選択された1種以上であることを特徴とする請求項13に記載のp34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤の癌に対する治療効果予測方法。
- 前記方法は、3)生物学的試料の癌細胞が増殖されると、p34の発現抑制剤または活性抑制剤の癌に対する治療効果が存在しないで、生物学的試料の癌細胞が増殖されないと、p34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤の治療効果が存在すると予測する段階を含むことを特徴とする請求項13に記載のp34遺伝子の発現抑制剤またはp34タンパク質の活性抑制剤の癌に対する治療効果予測方法。
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