Anti-cancer characteristics and ototoxicity of platinum(II) amine complexes with only one leaving ligand.

Jerry D Monroe,Hannah K Ruggles,Kevin M Williams,Heidi L Hruska,Michael E Smith,Reza Yousefi

doi:10.1371/journal.pone.0192505

Abstract

Unlike cisplatin, which forms bifunctional DNA adducts, monofunctional platinum(II) complexes bind only one strand of DNA and might target cancer without causing auditory side-effects associated with cisplatin treatment. We synthesized the monofunctional triamine-ligated platinum(II) complexes, Pt(diethylenetriamine)Cl, [Pt(dien)Cl]+, and Pt(N,N-diethyldiethylenetriamine)Cl, [Pt(Et2dien)Cl]+, and the monofunctional heterocyclic-ligated platinum(II) complexes, pyriplatin and phenanthriplatin, and compared their 5’-GMP binding rates, cellular compartmental distribution and cellular viability effects. A zebrafish inner ear model was used to determine if the monofunctional complexes and cisplatin caused hearing threshold shifts and reduced auditory hair cell density. The four monofunctional complexes had varied relative GMP binding rates, but similar cytosolic and nuclear compartmental uptake in three cancer cell lines (A549, Caco2, HTB16) and a control cell line (IMR90). Phenanthriplatin had the strongest effect against cellular viability, comparable to cisplatin, followed by [Pt(Et2dien)Cl]+, pyriplatin and [Pt(dien)Cl]+. Phenanthriplatin also produced the highest hearing threshold shifts followed by [Pt(dien)Cl]+, [Pt(Et2dien)Cl]+, cisplatin and pyriplatin. Hair cell counts taken from four regions of the zebrafish saccule showed that cisplatin significantly reduced hair cell density in three regions and phenanthriplatin in only one region, with the other complexes having no significant effect. Utricular hair cell density was not reduced by any of the compounds. Our results suggest that placing greater steric hindrance cis to one side of the platinum coordinating center in monofunctional complexes promotes efficient targeting of the nuclear compartment and guanosine residues, and may be responsible for reducing cancer cell viability. Also, the monofunctional compounds caused hearing threshold shifts with minimal effect on hair cell density, which suggests that they may affect different pathways than cisplatin.

Highlights

A major side-effect of platinum-based anticancer drugs is damage to auditory hair cells [1,2,3,4]
Platinum-based drugs currently approved by the FDA, e.g., cisplatin, oxaliplatin and carboplatin, have diamine ligands with either a bidentate chelating ligand or two ligands that can be replaced by water through aquation reactions [5]
Our results suggest that the platinum complexes induce auditory threshold shifts in this series: pyriplatin < cisplatin < [Pt (Et2dien)Cl]+ % [Pt(dien)Cl]+ < phenanthriplatin, with the mean TTS for pyriplatin and phenanthriplatin being, respectively, 6 and 13 dB (Fig 6)

Summary

Introduction

A major side-effect of platinum-based anticancer drugs is damage to auditory hair cells [1,2,3,4]. Platinum-based drugs currently approved by the FDA, e.g., cisplatin, oxaliplatin and carboplatin, have diamine ligands with either a bidentate chelating ligand or two ligands that can be replaced by water through aquation reactions [5]. These chemotherapeutic agents form bonds with DNA that promote cytotoxicity [6,7,8]. These drugs undergo aquation of their leaving groups enabling them to react with DNA and proteins [6, 9,10] They usually react with guanine bases and typically form bifunctional 1,2-intrastrand cross-links [11]. An unfortunate consequence is often hearing loss caused by apoptotic damage to auditory hair cells [12,13,14,15,16]

Methods

Results

Conclusion