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- ItemGenotoxic anti-cancer agents and their relationship to DNA damage, mitosis, and checkpoint adaptation in proliferating cancer cells(M D P I A G, 2014) Swift, Lucy H.; Golsteyn, RoyWhen a human cell detects damaged DNA, it initiates the DNA damage response (DDR) that permits it to repair the damage and avoid transmitting it to daughter cells. Despite this response, changes to the genome occur and some cells, such as proliferating cancer cells, are prone to genome instability. The cellular processes that lead to genomic changes after a genotoxic event are not well understood. Our research focuses on the relationship between genotoxic cancer drugs and checkpoint adaptation, which is the process of mitosis with damaged DNA. We examine the types of DNA damage induced by widely used cancer drugs and describe their effects upon proliferating cancer cells. There is evidence that cell death caused by genotoxic cancer drugs in some cases includes exiting a DNA damage cell cycle arrest and entry into mitosis. Furthermore, some cells are able to survive this process at a time when the genome is most susceptible to change or rearrangement. Checkpoint adaptation is poorly characterised in human cells; we predict that increasing our understanding of this pathway may help to understand genomic instability in cancer cells and provide insight into methods to improve the efficacy of current cancer therapies.
- ItemSynthesis, characterization and anticancer activities of cationic η6-p-cymene ruthenium(II) complexes containing phosphine and nitrogenous ligands(Elsevier, 2022) Guimaraes, Ivelise D. L.; Marszaukowski, Flávia; Rutka, Priscila B.; Borge, Luis F.; Ribeiro, Renan A. P.; Ricardo de Lazaro, Sergio; Castellen, Patrícia; Sagoe-Wagner, Araba; Golsteyn, Roy M.; Boeré, René T.; Wohnrath, KarenRuthenium-based anticancer agents have created a center of attention in the field of inorganic medicinal chemistry. The first fully characterized cationic ruthenium(II)-arene complexes [Ru(η6-p-cymene) (PAr3)LNCl]+ with highly lipophilic PAr3 ligands where Ar = 3,5-((CH3)3C)2C6H3– (L1), 3,5-(CH3)2C6H3– (L2), 4-CH3O-3,5-(CH3)2C6H2– (L3) and 4-CH3O-C6H4– (L4) with N = 3-methylpyridine (1–4, respectively), or L4 and 4-methylpyridine (5), or L4 and CH3CN (6) were obtained (yields 67–91%) as solids stable to light and air. Electrical conductance indicates that all the complexes are 1:1 electrolytes in solution. Their composition and purity have been unambiguously established by single-crystal X-ray diffraction, NMR spectroscopy and elemental analysis. The coordination geometries are uniform for all six complexes and each structure consist of a unipositive complex cation bearing the phosphine ligands L1-L4 and LN = 3-methylpyridine, 4-methylpyridine or CH3CN attached to the organometallic fragment. The equivalent unit cell volumes per formula unit decrease with 1 > 3 > 2 > 4 > 5 > 6, accurately reflecting the decreasing sizes of the phosphines L1-L4, and a greater occupied volume for 3-methyl- vs. 4-methylpyridine, and the smallest volume contribution from CH3CN. Electrochemical studies showed mixed electrochemical mechanisms (EC/ECE) from partial substitution of p-cymene by CH3CN ligands from the solvent. A large electrochemical stability window (>2.2 V) for Ru(II) was observed extending beyond the physiological E° range. The complexes were cytotoxic against human cancer cell lines in vitro, and some complexes altered cell morphology.