Abstract
BackgroundAlthough two novel synthesized compounds with tri-aryl structures; 3-(4-chlorophenyl)-5-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (A) and 3,5-bis-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (B) have been previously demonstrated to possess remarkable anti-breast cancer activity, their cardiotoxicity remains a major concern due to their mechanism of action. To address this concern, we assessed the ability of these compounds to cause toxicity towards H9c2 cardiomyocytes as an in vitro model of cardiotoxicity.MethodsCytotoxic activity of both compounds was explored in vitro on H9c2 cells using MTT assay. Annexin V/PI method, intracellular ROS determination and mitochondrial membrane potential assay were applied to elucidate the mechanism of action of the cell death.ResultsMTT assay revealed a concentration- and time-dependent cardiotoxicity. Findings of apoptosis by double staining with annexin V and propidium iodide divulged no cell death including apoptosis and necrosis at the concentration that were effective to inhibit cancer cells proliferation (10 μM) at 24 and 48 h. Furthermore, flow cytometric measurement of membrane potential and ROS determination using DCFH-DA verified the safe concentration of the compounds against H9c2 cells with no cardiotoxic effect. However, the higher concentration of the compounds could induce cell death through ROS-mediated mitochondrial dysfunction.ConclusionsAltogether, the results represented two novel chemical molecules possessing anti-breast cancer activity with minimum cardiac side effect.
Highlights
Two novel synthesized compounds with tri-aryl structures; 3-(4-chlorophenyl)-5-(4fluorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (A) and 3,5-bis-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1,2,4oxadiazole (B) have been previously demonstrated to possess remarkable anti-breast cancer activity, their cardiotoxicity remains a major concern due to their mechanism of action
We previously reported the apoptotic activity of the two compounds; 3-(4-chlorophenyl)-5-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (A) and 3,5bis-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (B) (Fig. 1) in the breast cancer cells via a COX-2 independent pathway [18], these compounds interacted with the active site of COX-2 enzyme [19]
Since generation of reactive oxygen species (ROS) activates mitochondrial-mediated apoptotic signaling pathway leading to caspase 3 activation and cardiac cell apoptosis, we further focused on the understanding of molecular mechanism underlying cardiotoxicity of two compounds
Summary
Two novel synthesized compounds with tri-aryl structures; 3-(4-chlorophenyl)-5-(4fluorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (A) and 3,5-bis-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1,2,4oxadiazole (B) have been previously demonstrated to possess remarkable anti-breast cancer activity, their cardiotoxicity remains a major concern due to their mechanism of action. To address this concern, we assessed the ability of these compounds to cause toxicity towards H9c2 cardiomyocytes as an in vitro model of cardiotoxicity. Cardiotoxicity induced by drugs has gained attention in the past few decades. High level of reactive oxygen species (ROS) due to oxidative stress can enfeeble cardiac cellular signaling pathways [14].
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