ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine

Publication date: October 2018Source: Biomedicine & Pharmacotherapy, Volume 106Author(s): Mahendra Seervi, Ankita Rani, Abhay K. Sharma, T.R. Santhosh KumarAbstractA dopamine receptor antagonist, Thioridazine (TDZ) is known for its cytotoxic activity against various cancers and its role in combinational chemotherapy is being actively investigated. Several molecular targets of TDZ have been studied to delineate its anticancer activities, with contrasting findings in different cancer types. Moreover, the underlying mechanism of cell death from TDZ treatment is not well defined. In the current study, we studied TDZ mediated cell death mechanism employing cervical cancer cells. TDZ treatment induced nuclear condensation, mitochondrial membrane potential loss, mitochondrial cytochrome c release, activation of caspase-9 and caspase-3 substantiating mitochondrial pathways of apoptosis in cells. TDZ induced ROS generation and up-regulation of ER stress linked proteins, such as CHOP, BiP etc. ER stress and apoptosis caused by TDZ were prevented by ROS inhibitor N-acetyl-L-cysteine (NAC) and protein synthesis inhibitor cycloheximide. In TDZ mediated cytocidal cellular process, autophagy acted as a cell survival factor as the inhibition of autophagy by 3-Methyladenine resulted in increased cell death. TDZ induced apoptosis was associated with decreased Bcl-2 expression and the overexpression of Bcl-2 resulted in inhibition of apoptosis. Studies in Bax-Bak knock-out cell model indicated ...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research