JP2016020328A - 抗がん剤 - Google Patents
抗がん剤 Download PDFInfo
- Publication number
- JP2016020328A JP2016020328A JP2015104903A JP2015104903A JP2016020328A JP 2016020328 A JP2016020328 A JP 2016020328A JP 2015104903 A JP2015104903 A JP 2015104903A JP 2015104903 A JP2015104903 A JP 2015104903A JP 2016020328 A JP2016020328 A JP 2016020328A
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- Prior art keywords
- ptb1
- double
- cells
- stranded sirna
- sir
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
【解決手段】PTB1を標的とする二本鎖siRNAまたは該二本鎖siRNAの発現ベクターを有効成分として含む、抗がん剤によって上記課題が解決される。
【選択図】図9
Description
(細胞培養)
ヒト大腸がん細胞株(DLD−1細胞およびWiDr細胞)は、10%(v/v)の熱不活化FBS(シグマ−アルドリッチ株式会社)および2mM L−グルタミンを添加したRPMI−1640培地中で、37℃、95%空気/5%CO2の雰囲気のインキュベーター内で培養した。ヒト単球細胞株(THP1細胞)およびヒト胃がん細胞株(MKN45細胞)は、DLD−1細胞やWiDr細胞と同じ培地中で、同様の条件下で培養した。なお、細胞はすべてJCRB生物資源バンク(Japanese Collection of Research Bioresorces)より購入した。
各細胞は、トランスフェクションの前日に0.5×105細胞/ウェル(10〜30%コンフルエント)となるように6ウェルプレートに播種した。成熟miR−124(mirVana(登録商標)miRNA mimic、アンビオン社製)、またはPTB1を標的とする二本鎖siRNA(siR−PTB1、ライフテクノロジーズ社製)および/若しくはPKM2を標的とする二本鎖siRNA(siR−PKM2、ライフテクノロジーズ社製)を細胞へのトランスフェクションに用いた。成熟miR−124の配列を、配列番号17に示す。siR−PTB1としては、ヒトPTB1をコードするmRNAの3’非翻訳領域に含まれる領域を標的配列とするsiR−PTB1−1(上記配列番号9と配列番号11とがアニールした二本鎖ポリヌクレオチドからなる)、およびヒトPTB1をコードするmRNAのORF領域に含まれる領域を標的配列とするsiR−PTB1−2(上記配列番号10と配列番号12とがアニールした二本鎖ポリヌクレオチドからなる)を用いた。siR−PKM2としては、上記配列番号15と配列番号16とがアニールした二本鎖ポリヌクレオチドを用いた。また、対照群としては配列番号18に示す非特異対照miRNAを用いた。
生存細胞の数は、トリパンブルー染色法により生細胞数を測定した。対照群における生存細胞数を100(%)とし、対照群の細胞数に対する試験群の生存細胞数の割合(細胞生存率)を求めた。細胞生存率が低い群ほど、細胞増殖抑制活性が高いことを示す。
動物実験プロトコルは、岐阜大学の動物実験福祉委員会によって承認された。
細胞または移植部位の組織を、氷冷した溶解バッファー(10mMトリス−HCl(pH7.4)、1%(w/v)NP−40、0.1%(w/v)デオキシコール酸、0.1%(w/v)SDS、150mM NaCl、1mM EDTA、および1%(w/v)プロテアーゼインヒビターカクテル(シグマ−アルドリッチ社)中でホモジナイズし、氷上で20分間静置した。ホモジネートを13,000rpmで20分間(4℃)遠心分離した後、上清を全細胞タンパク質試料として採取した。試料中のタンパク質含有量は、DCプロテインアッセイキット(バイオラッド社)を用いて測定した。
細胞のアポトーシスによる形態学的特徴を評価するため、DLD−1細胞を、トランスフェクション後72時間で回収した。ヘキスト(5μg/ml)を用いて細胞を37℃で1時間染色し、リン酸緩衝生理食塩水で洗浄後に再懸濁し、ガラススライド上にピペットで滴下し、顕微鏡(オリンパス社)を用いた蛍光顕微鏡法により検査した。顕微鏡観察の結果、凝縮および/または断片化した核を持つ細胞は、アポトーシスを起こしているものと評価した。
統計分析はグラフパッドプリズムソフトウェアシステム(グラフパッドソフトウェア社)を用いて行った。in vitro実験については、両側スチューデントt検定により統計有意性を評価した。in vivo実験(ヌードマウス実験)については、マンホイットニーU検定によりデータを比較した。値は平均±標準偏差として示した。P値<0.05を統計的に有意であるとみなした。
(細胞増殖抑制活性)
DLD−1細胞またはWiDr細胞をmiR−124で72時間処理した場合の、対照群(図中の「C」)に対する生存細胞の割合を図2に示す。また、DLD−1細胞またはWiDr細胞をsiR−PTB1−1で72時間処理した場合の、対照群(図中の「C」)に対する生存細胞の割合を図3に示す。図2および図3に示すように、DLD−1細胞およびWiDr細胞のいずれにおいても、siR−PTB1はmiR−124よりも細胞増殖抑制活性が高いことがわかる。なお、siR−PTB1−2で処理した場合も同様の傾向が認められた。特にDLD−1細胞においては、siR−PTB1の効果は顕著であり、40nMのmiR−124よりも5nMのsiR−PTB1の方が細胞増殖抑制活性が高いことがわかる。
DLD−1細胞またはWiDr細胞をmiR−124で72時間処理した場合の、PTB1の発現をウェスタンブロットにて確認した結果を図5に示す。また、DLD−1細胞またはWiDr細胞をsiR−PTB1−1で72時間処理した場合の、PTB1、アポトーシス関連タンパク質、またはオートファジー関連タンパク質をウェスタンブロットにて確認した結果を図6に示す。図5と図6との比較から、DLD−1細胞およびWiDr細胞のいずれにおいても、siR−PTB1では、miR−124よりも低濃度でPTB1の発現を強く抑制していることが分かる。なお、siR−PTB1−2で処理した場合も同様の傾向が認められた。
5nMのsiR−PTB1−1でDLD−1細胞を72時間処理し、ヘキスト核染色を行って撮影した顕微鏡像(100倍)を図8に示す。siR−PTB1処理をした群(右)ではアポトーシスによる核の分断化(矢印)が認められるが、対照群(左)では核の分断化は認められない。
ヒトがん細胞を移植したヌードマウスを用い、siR−PTB1−1によるin vivoでの細胞増殖抑制活性およびPTB1の発現抑制を評価した結果を図9〜11に示す。
DLD−1細胞またはWiDr細胞をsiR−PKM2で72時間処理した場合の、対照群に対する生存細胞の割合を図12に、PKM2の発現をウェスタンブロットにて確認した結果を図13に示す。siR−PKM2処理によりPKM2の発現が抑制されることが確認された。図3と図12との比較により、DLD−1細胞およびWiDr細胞において、siR−PTB1の細胞増殖抑制活性は、siR−PKM2よりも高いことが分かる。
DLD−1細胞をsiR−PTB1(5nM)、siR−PKM2(5nM)、または併用(siR−PTB1(5nM)およびsiR−PKM2(5nM))で48時間処理した場合における、対照群に対する生存細胞の割合を図16に示す。48時間処理でも、siR−PTB1−1、siR−PTB1−2またはsiR−PKM2処理群では対照群と比較して生存細胞の割合が低下していた。驚くべきことに、siR−PTB1とsiR−PKM2とを併用することにより、各々を単独で処理した場合よりもさらに生存細胞の割合が低下していた。siR−PTB1−1とsiR−PKM2とを併用した群の生存細胞の割合と、siR−PTB1−1単独で処理した群の生存細胞の割合には統計的に有意な差があり、併用効果が確認された。
PTB1を標的とする二本鎖siRNAのパッセンジャー鎖である。
〔配列番号:10〕
PTB1を標的とする二本鎖siRNAのパッセンジャー鎖である。
〔配列番号:11〕
PTB1を標的とする二本鎖siRNAのガイド鎖である。
〔配列番号:12〕
PTB1を標的とする二本鎖siRNAのガイド鎖である。
〔配列番号:15〕
PKM2を標的とする二本鎖siRNAのパッセンジャー鎖である。
〔配列番号:16〕
PKM2を標的とする二本鎖siRNAのガイド鎖である。
〔配列番号:18〕
陰性対照miRNAである。
Claims (5)
- PTB1を標的とする二本鎖siRNAまたは該二本鎖siRNAの発現ベクターを有効成分として含む、抗がん剤。
- 前記二本鎖siRNAのガイド鎖が配列番号1で示される塩基配列における連続する16〜27塩基に相補的な配列を含む、請求項1に記載の抗がん剤。
- 前記二本鎖siRNAのガイド鎖が配列番号11または配列番号12で示される塩基配列からなる、請求項1または2に記載の抗がん剤。
- 前記がんが、大腸がん、胃がん、食道がん、乳がん、および白血病からなる群から選択される、請求項1〜3のいずれか1項に記載の抗がん剤。
- PKM2を標的とする二本鎖siRNAまたは該二本鎖siRNAの発現ベクターをさらに含む、請求項1〜4のいずれか1項に記載の抗がん剤。
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J. BIOL. CHEM., 2008, VOL.283, NO.29, PP.20277-20287, JPN6018046203 * |
ONCOGENESIS, 2014 JAN, VOL.3, NO.E84, PP.1-8, JPN6018046201 * |
THERANOSTICS, 2014 FEB, VOL.4, NO.5, PP.487-497, JPN6018046205 * |
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