Chemosensitizer effect of cisplatin-treated bladder cancer cells by phenazine-5,10-dioxides

• Published in: Environmental toxicology and pharmacology Vol. 69; pp. 9 - 15
• Main Authors: Hernández, Paola, Alem, Diego, Nieves, Marcos, Cerecetto, Hugo, González, Mercedes, Martínez-López, Wilner, Lavaggi, María Laura
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2019; Elsevier Science Ltd
• Subjects: Bladder; Bladder cancer; Cancer; Cell cycle; Chromosome aberrations; Cisplatin; Combined treatment; Derivatives; Dioxides; Histone deacetylase; Invasiveness; Phenazine; Phenazine dioxide; Sensitizer; Toxicity; Tumors; Histone deacetylase; Bladder cancer; Phenazine dioxide; Cisplatin; Sensitizer
• ISSN: 1382-6689; 1872-7077
• DOI: 10.1016/j.etap.2019.03.015

•Phenazines 2c and 3a emerged as chemosensitizer agents to bladder cancer cells.•The HDAC inhibitory activity appears as one of the mechanism of action of 2c.•Phenazine dioxide 3a induced a sensitizer effect independent from HDAC inhibition.•Phenazine dioxides 2c and 3a presented low toxicity levels against normal cells.•Compounds 2c and 3a are good scaffolds for the further design of sensitizer agents. We determined the chemosensitizer effect of phenazine dioxide derivatives to cisplatin and the possible mechanism of action on bladder cancer cells. Anti-proliferative activity of nine phenazine dioxide derivatives in presence or absence of cisplatin was evaluated in two bladder tumor human cells T24 and 253 J and one non tumor cell line V79-4. The sensitizer effect of the combined treatment was determined by chromosomal aberrations and micronucleus test. A possible mechanism of action of the sensitizer compounds as HDACi was also investigated.The phenazine dioxide 2c combined with cisplatin induced a cell cycle arrest on bladder cancer cells and resensitize the invasive and cisplatin resistant 253 J cell line. The HDAC inhibitory activity appears as one of the mechanism of action of the compound. The low toxicity levels against normal cells point out the phenazine dioxide derivative 2c as a very good scaffold for further design of HDACi sensitizer agents.