Abstract
Therapeutic options for advanced stage cholangiocellular carcinoma (CCC) are very limited as of today and patients carry an exceptionally poor overall prognosis. In recent years, increasing evidence has been accumulated to suggest that malignant cells widely show increased intrinsic ROS levels and exhibit altered redox profiles as compared to normal counterparts, opening up potential avenues for therapeutic intervention. This study provides preclinical experimental evidence of therapeutic activity of the curcumin analog EF24 in cholangiocarcinoma models. In CCC cell lines, EF24 inhibited cell viability and induced apoptosis through excessive ROS generation. Moreover, administration of EF24 led to depletion of total intracellular GSH levels, induced mitochondrial depolarization, and abrogated STAT3 phosphorylation. Of interest, these effects were readily averted by treating the cells with exogenous antioxidants such as N-acetyl cysteine (NAC) or glutathione monoethyl ester (GEE). In vivo, EF24, solubilized using a cyclodextrin formulation, significantly suppressed the growth of tumor xenografts without exhibiting any toxic adverse effects. Immunohistochemical analysis of extracted tumor tissues demonstrated reduced nuclear staining for Ki-67 and downregulation of phospho-STAT3 as well as strong staining for oxidative stress biomarker 8-OHdG. Therefore, the data presented here suggest EF24 as potential therapeutic compound against CCC which might act at least to some extent through ROS-induced oxidative damage, subsequently inducing apoptosis. Further evaluation of this approach should be carried out in future follow-up studies.
Highlights
Cholangiocellular carcinoma (CCC) is the second most common cancer of the hepatobiliary tract and arises from malignant transformation of cholangiocytes lining intra- and extrahepatic bile ducts [1, 2]
Net cell growth of established cholangiocarcinoma cell lines SNU478 and HuCC-T1 was evaluated in the presence of increasing concentrations of EF24 or its parent compound curcumin, respectively, by means of cell viability (MTS) assays
In order to better understand the mechanism underlying the observed reduction of in vitro net Cholangiocellular carcinoma DMSO (CCC) cell growth caused by treatment with EF24, we evaluated its effect on apoptosis using Annexin binding assays
Summary
Cholangiocellular carcinoma (CCC) is the second most common cancer of the hepatobiliary tract and arises from malignant transformation of cholangiocytes lining intra- and extrahepatic bile ducts [1, 2]. ROS stress in cancer cells and its potential therapeutic implications have emerged as a promising area of research. Due to increased metabolic activity, oncogenic stimulation, and mitochondrial malfunction, cancerous cells produce higher levels of ROS and are constantly in a state of increased chronic oxidative stress as compared to noncancerous counterparts [4,5,6,7,8]. Moderate increase in ROS production promotes carcinogenesis and cancer progression due to their stimulating effects on cell growth and proliferation [9,10,11,12,13,14], excessive production and accumulation of ROS can cause irreversible cellular damage triggering cell death [15]. Of interest, increased basal oxidative stress in cancerous and transformed cells renders them highly dependent on antioxidant systems to counteract the damaging effects of Journal of Oncology
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