A trans-Pt(ii) hedgehog pathway inhibitor complex with cytotoxicity towards breast cancer stem cells and triple negative breast cancer cells. Issue 47 (16th November 2022)

• Record Type: Journal Article
• Authors: Ryan, Aisling L.; Northcote-Smith, Joshua; McKeon, Aoife; Roe, Andrew; O'Dowd, Paul; Twamley, Brendan; Ní Chonghaile, Triona; Suntharalingam, Kogularamanan; Griffith, Darren M.
• Is Part Of: Dalton transactions. Volume 51:Issue 47(2022)
• Page Start: 18127
• Page End: 18135
• Publication Date: 2022-11-16
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/d2dt02865d
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : Hedgehog pathway inhibitor ligand enhances cytotoxicity of trans -Pt(ii ) complex towards breast cancer stem cells and triple negative breast cancer cells. Abstract : The first example of a Pt complex of GANT61, a hedgehog (Hh) pathway inhibitor is reported. Reaction of cis -[Pt(ii )Cl2 (dmso)2 ] with one equivalent of 4-pyridine carboxaldehyde (4-PCA, control ligand) or one equivalent of GANT61 (Hh pathway inhibitor) in acetone at rt for 30 minutes afforded trans -[Pt(ii )Cl2 (dmso)(4-PCA)] (1 ) and trans -[Pt(ii )Cl2 (dmso)(GANT61)] (2 ) respectively, where 4-PCA and GANT61 are N-donor ligands. The structures of 1 and 2 were fully characterised by elemental analysis, 1 H NMR, 13 C NMR and IR spectroscopy and X-ray crystallography. 1 and 2 undergo isomerisation from trans - to cis -in solution and therefore the biological activity of 2 is also associated with the cis -configuration. The in vitro cytotoxicity data show that 2 is a potent inhibitor of the growth of breast CSC-depleted HMLER and breast CSC-enriched HMLER-shEcad cells. Furthermore 2 markedly reduced the size and viability and significantly reduced the number of CSC-enriched HMLER-shEcad mammospheres formed. 2 also induced apoptosis with low micromolar IC50 values against two triple negative breast cancer lines, MDA-MB-231 (MDA231) and BT549. 2, which possesses the Hh pathway inhibitor GANT61 as an N donor ligand exhibits far superior anti-CSC activity including in the CSC-enriched mammosphere model and activity against TNBC cells as compared to its control analogue, the trans -Pt(ii ) 4-PCA complex 1 . The trans -Pt GANT61 complex 2 has also been shown to cause DNA damage and inhibit the Hh pathway at the level of GLI.