Abstract
Resistance to platinum drugs (used in >50% of cancer chemotherapies) is a clinical problem. Other precious metal complexes with distinct mechanisms of action might overcome this. Half-sandwich organometallic complexes containing arene or cyclopentadienyl (Cp) ligands show promise. We screened two iridium(iii) complexes [Ir(CpXbiph)(ppy)Cl] (ZL49, 1, ppy = phenylpyridine) and [Ir(CpXph)(azpyNMe2)Cl]PF6 (ZL109, 2, azpyNMe2 = N,N-dimethylphenylazopyridine) in 916 cancer cell lines from 28 tissue types. On average, complex 2 was 78× more potent than 1, 36× more active than cisplatin (CDDP), and strongly active (nanomolar) in patient-derived ovarian cancer cell lines. RNA sequencing of A2780 ovarian cells revealed upregulation of antioxidant responses (NRF2, AP-1) consistent with observed induction of reactive oxygen species (ROS). Protein microarrays, high content imaging and cell cycle analysis showed S/G2 arrest, and late-stage DNA damage response without p53 requirement. The triple-negative breast cancer cell line OCUB-M was highly sensitive to 2 as were cell lines with KIT mutations. Complex 2 exhibits a markedly different pattern of antiproliferative activity compared to the 253 drugs in the Sanger Cancer Genome database, but is most similar to osmium(ii) arene complexes which share the same azopyridine ligand. Redox modulation and DNA damage can provide a multi-targeting strategy, allowing compounds such as 2 to overcome cellular resistance to platinum anticancer drugs.
Highlights
IntroductionUniversity of Edinburgh, UK f Department of Chemistry and Chemical Engineering, Qufu Normal University, China † Electronic supplementary information (ESI) available
Introduction a Department ofChemistry, University of Warwick, UK
We have discovered potent antiproliferative activity for organoOs(II) and organo-Ir(III) complexes by phenotypic screening and have shown that screening in the National Cancer Institute (NCI-60) and Sanger 800+ panel of cancer cell lines when combined with transcriptomics, reactive oxygen species (ROS), protein micro-arrays, high content imaging and other assays can provide valuable insight into their mechanism of action (MoA).[9,10]
Summary
University of Edinburgh, UK f Department of Chemistry and Chemical Engineering, Qufu Normal University, China † Electronic supplementary information (ESI) available. The square-planar platinum drugs cisplatin (CDDP), carboplatin and oxaliplatin are used in over 50% of cancer chemotherapies, but intrinsic and acquired resistance represent major clinical problems across cancer indications. CDDP has a primary mechanism of action (MoA) which involves DNA targeting, induction of DNA bending, and apoptosis.[1] Other precious metal complexes might be able to overcome resistance if they have different MoAs. CDDP has a primary mechanism of action (MoA) which involves DNA targeting, induction of DNA bending, and apoptosis.[1] Other precious metal complexes might be able to overcome resistance if they have different MoAs This appears to be the case for platinum drug oxaliplatin and candidate drug phenanthriplatin, which are not cross-resistant with CDDP. Oxaliplatin is classified as a DNA alkylating agent like CDDP, recent evidence
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