Disruption of SSBs repair to combat platinum resistance via the JWA-targeted Pt(IV) prodrug conjugated with a wogonin derivative

An octahedral Pt (IV) prodrug, Cis-wog, containing a wogonin derivative as a bioactive axial ligand was designed and prepared to suppress DDR (DNA damage repair)-related proteins. In vitro biological studies indicated that a Pt (IV) prodrug with axially functional groups (Cis-wog) showed cytotoxicit...

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Veröffentlicht in:Pharmazie 2020-03, Vol.75 (2), p.94-101
Hauptverfasser: Wang, Xing, Li, Leyi, Pei, Sinan, Zhu, Qian, Chen, Feihong
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Sprache:eng
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Zusammenfassung:An octahedral Pt (IV) prodrug, Cis-wog, containing a wogonin derivative as a bioactive axial ligand was designed and prepared to suppress DDR (DNA damage repair)-related proteins. In vitro biological studies indicated that a Pt (IV) prodrug with axially functional groups (Cis-wog) showed cytotoxicity superior to cisplatin and reversed its resistance against two pairs of cisplatin sensitive and resistant cell lines. Further mechanistic research revealed that the powerful antitumor activity of Cis-wog resulted from its suppression of JWA and its multi-interaction with XRCC1 to repair DNA single strand breaks (SSBs) caused by the introduction of wogonin. It is concluded that Cis-wog is a promising cytotoxic agent, which could be used for enhancing the antitumor activity of its corresponding Pt(II)-based drugs and reversing cisplatin resistance via decaying JWA-mediated SSBs repair pathways and inducing apoptosis.
ISSN:0031-7144
DOI:10.1691/ph.2020.9815