単核および二核DNA光スイッチ複合体の細胞毒性,吸収,細胞応答,およびプロテオミクスの探索

Paul J Jarman¹, Felicity Noakes^1,2, Simon Fairbanks²

¹Department of Biomedical Science , University of Sheffield , Sheffield S10 2TN , U.K.

Journal of the American Chemical Society

|January 1, 2019

まとめ

新しい金属複合体はプラチナ耐性がん治療として有望ですこれらの化合物は,アポトーシスではなく,腫瘍による急速な細胞死を引き起こし,薬剤耐性腫瘍に対する新しい治療戦略を提供します.

科学分野:

協調化学
化学生物学
癌研究

背景:

プラチナベースの化学療法に対する薬剤耐性は主要な臨床的課題であり,しばしばアポトーシス回避に関連しています.
金属複合体は代替的な抗がん戦略を提供します特にDNAと相互作用するものです
新しい薬剤によって誘発される細胞死亡のメカニズムを理解することは,治療開発にとって極めて重要です.

研究の目的:

異なる構造を持つ新しいルテニウム複合体のDNA結合モードと細胞毒性効果を比較する.
これらの複合体によって誘発される細胞死亡メカニズム,特にプラチナ耐性がん細胞を調査する.
これらの複合体の可能性を新しい化学療法薬として探求する.

主な方法:

単核および二核ルテニウム複合体の合成と特徴付け.
DNAの相互作用モード (インターケレーション対グリューブ結合) と細胞毒性の評価
細胞死亡のタイミングを監視するために,ライトスイッチ効果を利用した生細胞顕微鏡.
複合体によって影響を受ける細胞経路を特定するための定量タンパク質解析

主要な成果:

構造的変更により,DNA結合はインターケレーションからグリューブ結合へと移行し,効力を低下させましたが,プラチナ抵抗は克服できませんでした.
すべての複合体は,典型的なアポプトシス経路をバイパスして,オンコシス経由で急速な細胞死を引き起こした.
プロテオミク解析により,酸化ストレスとDNA修復に関連する細胞反応が明らかになった.

結論:

これらの複合体のプラチナ耐性における主要な要因は,DNA結合モードではありません.
オンコシスの誘導は,がん治療のための新しい非アポプトティック細胞死機構を表しています.
これらのルテニウム複合体は耐性がんに対する新しい化学療法薬の開発に有望な手がかりです

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