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Introduction
Lung cancer remains the leading cause of cancer-associated mortality worldwide, due to poor prognosis, high resistance to therapy and a low survival rate (1). Human non-small cell lung cancer (NSCLC) constitutes ≥80% of patients with lung cancer and includes adenocarcinoma, squamous cell carcinoma and large-cell carcinoma (2). Despite the abundance of available chemotherapeutic approaches, current treatments often lead to severe resistance and side effects (3). Therefore, it is necessary to develop a novel and alternative small molecule drug to provide effective chemotherapy with good efficacy and low toxicity.
Compounds composed of epoxy groups have become an attractive target for chemotherapy development (4). Previously, a triepoxide derivative called teroxirone, proved an effective treatment for patients recovering from leukemia and lymphoma (4,5). Furthermore, a previous study has demonstrated that the tumor suppressor p53 regulates teroxirone-induced apoptosis in human NSCLC cells by damaging cellular DNA (6). Despite the distinctive inhibitory effects demonstrated in cell and animal models, the targets and underlying mechanisms of teroxirone, which lead to p53 activation and final cell growth inhibition, are not yet understood (6). As a regulatory mediator, apoptosis serves to eliminate damaged cells without injuring the surrounding cells (7). Thus, to further understand the detailed mechanisms regarding the onset of apoptosis, the present study assessed mitochondrial functions during p53-dependent apoptosis. The results of the present study demonstrated that teroxirone activated reactive oxygen species (ROS), and that mitochondrial function was impaired as a result of teroxirone treatment, which contributed to cytotoxic effects. Pretreatment of ROS scavengers recovered cell viability by restoring mitochondrial function, reducing DNA damage and attenuating apoptotic characteristics. Thus, the efficacy of teroxirone by apoptotic cell death depended on the generated ROS following the disruption of the membrane potential cascade. The present study also provided further information on the apoptotic mechanisms that may lead to a novel perspective of triepoxides.
Materials and methods
Cell culture
H460 (HTB177™), H1299 (CRL5803™) and A549 (CCL185™) human NSCLC cells were purchased from the American Type Culture Collection (Manassas, VA, USA) and maintained in Dulbecco's modified Eagle's medium (DMEM; Sigma-Aldrich; Merck Millipore, Darmstadt, Germany). All cultured cells were supplemented with L-glutamine, sodium pyruvate and cultured with 10% heat-inactivated fetal bovine serum (FBS; Invitrogen; Thermo Fisher Scientific, Inc., Waltham, MA, USA) in 5% CO2...