Abstract
Disulfiram (DSF) is a well-known drug for alcohol abuse. In recent decades, DSF has been demonstrated to exhibit anti-tumor activity; DSF chelated with copper shows enhanced anti-tumor effect. Our goal was to explore the effect of DSF/Cu complex on the growth and metastasis of gastric cancer (GC) in vitro and in vivo. DSF/Cu complex suppressed the proliferation, migration of MKN-45 and BGC-823 GC cells. Furthermore, DSF/Cu treatment reduced the tumor volume in GC mouse models with a tumor suppression rate of 48.24%. Additionally, DSF/Cu induced apoptosis in vitro in MKN-45 and BGC-823 GC cells in a dose- and time-dependent manner as well as in vivo in the xenograft tumor mouse model. Furthermore, DSF/Cu induced autophagy and autophagic flux in MKN-45 and BGC-823 cells, increased the expression of autophagy-related Beclin-1 and LC3 proteins in vivo. Additionally, DSF/Cu suppressed aerobic glycolysis and oxidative phosphorylation by reducing oxygen consumption rate and extracellular acidification rate, respectively, in MKN-45 and BGC-823 cells. Treatment with DSF/Cu induced oxidative stress and DNA damage response by elevating the reactive oxygen species levels; increasing the expression of P53, P21, and γ-H2AX proteins; and inhibiting Wnt/β-catenin signaling in vitro and in vivo. Thus, DSF/Cu suppressed the growth and metastasis of GC cells via modulating the stress response and Wnt/β-catenin signaling. Hence, DSF may be used as a potential therapeutic agent for the treatment of GC.
Highlights
In 2018, gastric cancer (GC) ranked fifth in among all cancers regarding incidence and third regarding cancer-related deaths globally [1]
DSF/Cu treatment inhibited the migration of MKN-45 and BGC-823 cells compared to dimethyl sulfoxide (DMSO) treatment
DSF is rapidly converted to diethyldithiocarbamate in the system, which forms a stable complex with Cu; the complex exhibits a stronger anti-tumor effect than DSF alone [18]
Summary
In 2018, gastric cancer (GC) ranked fifth in among all cancers regarding incidence and third regarding cancer-related deaths globally [1]. In China, GC occupied the second and third rank in terms of cancer incidences and deaths, respectively, in 2015 [2]; it was associated with the highest recorded morbidity and mortality in 2013 in Gansu province [3]. Different management techniques and comprehensive therapies have been used for treating GC, their clinical benefits remain unsatisfactory [4]. Only a few patients with GC are diagnosed at the early stages of the disease. Metastasis remains the dominating cause of deaths in majority of the cases. In GC patients with metastasis, a 5-year survival rate has been reported to be only 5% [5]. Drugs with high efficacy and low toxicity are required for GC treatment
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