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

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.

A highly X-ray sensitive iridium prodrug for visualized tumor radiochemotherapy

“…3d, the SER of the designed prodrug Ir-NB was much higher than that of cisplatin (SER: 4.36) and other metalbased RSs reported in the literature. [30][31][32][33][34] These results indicated that the cancer-targeting delivery system facilitates the sensitization efficiency of the RS in curing malignant cells. The synergistic effect was further conrmed by the clonogenic survival assay ( Fig.…”

A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(ii) metallo-intercalator

“…The concentration required for radiosensitization by Ru1 offers a significant improvement over previous work using the multi-intercalator [Ru(dppz) 2 (PIP) 2+ ] 23 and is similar to more cytotoxic Ru(arene)-halide monocationic complexes, which – like cisplatin – rely upon metal-centred reactivity and the formation of coordination bonds with DNA. 56 …”

Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells

“…Several ruthenium complexes exhibit potent cytotoxic activity to cancer cells [ 27 – 29 ]. Moreover, selected ruthenium complexes are under phase I or II clinical trials, with promising results [ 30 , 31 ].…”