JP7016883B2 - リンゴ酸-アスパラギン酸シャトル抑制剤および抗癌剤を有効成分として含有する癌の予防および治療用薬学的組成物 - Google Patents
リンゴ酸-アスパラギン酸シャトル抑制剤および抗癌剤を有効成分として含有する癌の予防および治療用薬学的組成物 Download PDFInfo
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Description
<1-1> MAS抑制による肺癌および黒色腫細胞の生長抑制効果の確認
リンゴ酸-アスパラギン酸シャトル(malate-aspartate shuttle,MAS)に含まれるタンパク質であるGATの亜型であるSLC25A11の発現を抑制したとき、癌細胞に対して増殖抑制効果を示すことができるかを確認しようとした。
癌細胞株でMASタンパク質の発現を抑制したとき、細胞生長が抑制されることを確認したので、細胞内ATP生産レベルを確認した。
MASタンパク質の発現レベルを抑制することを通じて癌細胞の生長抑制効果を示すことができることを細胞レベルで確認したので、以後、生体内レベルでも癌生長抑制効果を示すことができるかを確認した。
<3-1>フェニルコハク酸(PSA)の処理による癌細胞の生長抑制効果の確認
siRNAまたはshRNAを利用してMASの発現を抑制したとき、試験管内および生体内の両方で癌の成長を抑制することができることを確認したが、癌細胞株の生長および腫瘍の成長を完全に抑制しないことを確認した。これより、MAS抑制剤を処理する場合では、効果的に癌を抑制することができるか否かを確認しようとした。
MAS抑制剤を処理したとき、癌細胞株の増殖を有意的に抑制できることを確認したので、MAS抑制剤の処理によって癌細胞内でATPレベルが減少するかを確認した。
他の抗癌剤として、b-oxidationを標的して癌細胞の増殖を抑制するものと知られているエトモキシルとMAS抑制剤のシナジー効果の有無を確認した。エトモキシルは、ミトコンドリア内膜の外部に位置するCPT-1(carnitine palmitoyltransferase-1)などの酵素に対する活性抑制剤として知られている。
Claims (4)
- リンゴ酸-アスパラギン酸シャトル(malate-aspartate shuttle,MAS)に含まれるタンパク質の発現又は活性に対する抑制剤を有効成分として含有する癌の予防および治療用薬学的組成物であって、
前記MASに含まれるタンパク質は、グルタミン酸-アスパラギン酸輸送体(GAT;glutamate-aspartate transporter)であり、
前記MASに含まれるタンパク質の活性に対する抑制剤は、フェニルコハク酸(Phenyl Succinic Acid)及びフタロン酸(Phthalonic Acid)からなる群から選択される1つ以上を含み、
前記MASに含まれるタンパク質の発現に対する抑制剤は、MASに含まれるタンパク質に対するsiRNAまたはshRNAの少なくとも1つ以上を含み、
前記癌は、黒色腫、乳癌、胃癌及び肝癌からなる群から選択される1つ以上を含む、癌の予防および治療用薬学的組成物。 - 前記siRNAは、配列番号1で表される塩基配列である正方向siRNAおよび配列番号2で表される塩基配列である逆方向siRNA;または配列番号3で表される塩基配列である正方向siRNAまたは配列番号4で表される塩基配列である逆方向siRNA;のうちいずれか一つであり、
前記shRNAは、配列番号5で表される塩基配列または配列番号6で表される塩基配列のうちいずれか一つ以上であることを特徴とする、請求項1に記載の癌の予防および治療用薬学的組成物。 - リンゴ酸-アスパラギン酸シャトル(malate-aspartate shuttle,MAS)に含まれるタンパク質の活性抑制剤としてのN-(1-ピレニル)マレイミド(N-(1-pyrenyl)maleimide)および抗癌剤としてのエトモキシルを含む、癌の予防および治療用薬学的組成物であって、
前記MASに含まれるタンパク質は、グルタミン酸-アスパラギン酸輸送体(GAT;glutamate-aspartate transporter)であり、
前記癌は、黒色腫、乳癌、胃癌及び肝癌からなる群から選択される1つ以上を含む、癌の予防および治療用薬学的組成物。 - 前記癌の予防および治療用薬学的組成物は、抗癌剤およびMAS抑制剤を1:10~500のモル比率で混合することを特徴とする、請求項3に記載の癌の予防および治療用薬学的組成物。
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KR10-2017-0048558 | 2017-04-14 | ||
KR20170048558 | 2017-04-14 | ||
PCT/KR2018/004344 WO2018190676A1 (ko) | 2017-04-14 | 2018-04-13 | 말산-아스파르트산 왕복수송 억제제 및 항암제를 유효성분으로 함유하는 암 예방 및 치료용 약학적 조성물 |
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EP (1) | EP3610866A4 (ja) |
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Non-Patent Citations (3)
Title |
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Biochemistry,1996年,Vol. 35,p. 8974-8980 |
Cell Death and Disease (2016) 7, e2511,doi:10.1038/cddis.2016.404 |
PLoS ONE 11(3): e0150675,2016年,doi:10.1371/journal.pone.0150675 |
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