Radiosensitisation of human colorectal cancer cells by ruthenium(II) arene anticancer complexes.

R Carter,CR Gallevo,MJ Romero,N Menezes,RA Sharma,Y Bark,PJ Sadler,A Westhorpe,A Habtemariam

doi:10.1038/srep20596

Abstract

Some of the largest improvements in clinical outcomes for patients with solid cancers observed over the past 3 decades have been from concurrent treatment with chemotherapy and radiotherapy (RT). The lethal effects of RT on cancer cells arise primarily from damage to DNA. Ruthenium (Ru) is a transition metal of the platinum group, with potentially less toxicity than platinum drugs. We postulated that ruthenium-arene complexes are radiosensitisers when used in combination with RT. We screened 14 ruthenium-arene complexes and identified AH54 and AH63 as supra-additive radiosensitisers by clonogenic survival assays and isobologram analyses. Both complexes displayed facial chirality. At clinically relevant doses of RT, radiosensitisation of cancer cells by AH54 and AH63 was p53-dependent. Radiation enhancement ratios for 5–10 micromolar drug concentrations ranged from 1.19 to 1.82. In p53-wildtype cells, both drugs induced significant G2 cell cycle arrest and apoptosis. Colorectal cancer cells deficient in DNA damage repair proteins, EME1 and MUS81, were significantly more sensitive to both agents. Both drugs were active in cancer cell lines displaying acquired resistance to oxaliplatin or cisplatin. Our findings broaden the potential scope for these drugs for use in cancer therapy, including combination with radiotherapy to treat colorectal cancer.

Highlights

Occurs, potentially stimulated by hypoxia[9,10]
To determine the optimal compounds to treat colorectal cancer cells in combination with radiotherapy, we measured the cytotoxicity without and with RT of 14 Ru(II) arene compounds in the colorectal cancer cell line, DLD1. This cell line was selected for the screening phase of the project since it contains a spectrum of mutations typical of colorectal cancer, including APC, p53, KRAS and PIK3CA, and because this cell line is relatively radioresistant compared to other colorectal cancer cell lines such as HCT11623
In order to demonstrate that the cytotoxicity of AH54 and AH63 is related to DNA damage induced by these drugs, we studied their effect on colorectal cancer cells lacking the ability to repair DNA damage

Summary

Introduction

Occurs, potentially stimulated by hypoxia[9,10] This may account for the apparently low toxicity of two Ru(III) agents, NAMI-A and KP1019, which have entered clinical trials in patients with cancer[11,12]. The proposed DNA binding mechanisms involve direct coordination to a DNA base (preferentially to guanine) accompanied by intercalation of extended arenes between neighboring base pairs in the double helix. Such interactions appear to contribute to the high potency of TB45 towards several human cancer cell lines compared to the less active isomer AH11517. On account of the clinical need for novel radiosensitisers for colorectal cancer described above, we focused our biological studies on human colorectal cancer

Methods

Results

Conclusion