Anticancer activities under reductive stress

MARTINEZ, VALERIA ROMINA; FERRER, EVELINA GLORIA; WILLIAMS, PATRICIA ANA MARÍA

Montevideo

Congreso; VII Latin American Meeting on Biological Inorganic Chemistry; 2021

Facultad de Química, Universidad de la República

Cellular oxidative stress is considered inducer of carcinogenesis. However, the associationof ROS with cancer is sometimes paradoxical. In this communication we show the role ofantioxidant compounds as anticancer agents. Candesartan and valsartan have been reportedto reduce levels of reactive oxygen species (ROS) in cancer cells [1,2]. We have determinedthat both antihypertensive drugs reduce cell viability on A549 lung cancer cells ( > 200 µM)and that their Zn(II) coordination complexes, [ZnCand(H2O)2].2H2O (ZnCand) and[ZnVals(H2O)2] (ZnVals) also reduced intracellular ROS contents and decrease cell viabilityat lower concentrations IC50, μM = 175 and 220, respectively, being non cytotoxic for normallung fibroblasts cell line (MRC5). The Zn complexes affected mitochondria membrane,increased of the pro- and anti- apoptotic protein ratio, Bax/Bcl-XL, and caspase-3 activation,by late apoptosis. Cancer cells show high ROS levels (1539 ± 35 IF/mg protein, A549) thannormal cells (809 ± 73 IF/mg protein, MCR5) and ROS are responsible of the maintenanceof cancer phenotype. Zn(II) complexes of telmisartan, azilsartan and losartan increasecellular ROS contents generating apoptosis in cancer cells. However, for ZnCand and ZnVals,reductive stress resulted responsible for apoptosis. To study the role of ROS in thecytotoxicity induced by the complexes, we measured the cell viability and ROS productionin A549 cells co-cultured with the IC50 concentrations of both complexes and increasingconcentrations of H2O2 (2-100 nM) or 5 mM NAC (N-acetylcysteine) for 24 h. The cytotoxiceffects induced by the decrease of ROS production were completely reversed by H2O2: thenormal growth was recovered maintaining ROS values similar to the control. The antioxidantcompound NAC exacerbated ROS reduction and increased cell death. These data suggest thatlow levels of ROS are also critical for the function of A549 cells and that ROS imbalancecould result in cancer cell death