title: 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.
authors: CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
authors: R
authors: R
authors: Carter
authors: CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
authors: A
authors: A
authors: Westhorpe
authors: Department of Chemistry, University of Warwick, UK.
authors: M J
authors: MJ
authors: Romero
authors: Department of Chemistry, University of Warwick, UK.
authors: A
authors: A
authors: Habtemariam
authors: CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
authors: C R
authors: CR
authors: Gallevo
authors: CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
authors: Y
authors: Y
authors: Bark
authors: CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
authors: N
authors: N
authors: Menezes
authors: Department of Chemistry, University of Warwick, UK.
authors: P J
authors: PJ
authors: Sadler
authors: CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
authors: R A
authors: RA
authors: Sharma
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000473:pathology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D011836:Radiation Tolerance / Q000187:drug effects*; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D012996:Solutions; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D009944:Organoplatinum Compounds; D012996:Solutions; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D012428:Ruthenium; D002945:Cisplatin