Abstract
Uveal melanoma (UM) is the most common primary intraocular carcinoma in adults. Cinobufagin, secreted by the Asiatic toad Bufo gargarizans, is a traditional Chinese medicine, widely used in tumor treatment. Here, we explored the potential antitumor function of cinobufagin and investigated its biochemical mechanisms in UM cells. The antitumor potential of cinobufagin was determined via cell viability, cell cycle, and apoptosis assays. Colony formation assays confirmed that cinobufagin exerted potent antitumor activity in a dose-dependent manner. We found that cinobufagin could induce cell apoptosis and upregulate the expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-9 in vivo and in vitro. In addition, after treatment with increased concentrations of cinobufagin, the intrinsic mitochondrial apoptosis pathway was also activated, which was demonstrated by increased cell apoptosis with increased expression of Bad and Bax, decreased expression of Bcl-2 and Bcl-xl, and reduced mitochondrial membrane potential (MMP) in OCM1 cells. Taken together, the results of this preclinical study suggest that cinobufagin can both inhibit cell survival and induce cell apoptosis in a dose-dependent manner in UM cells, which provides new insights into the biochemical mechanism of cinobufagin and its potential as a future chemotherapeutic agent for UM.
Highlights
Uveal melanoma (UM) represents the most frequently occurring primary intraocular malignant carcinoma in adults, with an annual incidence rate of 5.1 cases per million
Another report showed that cinobufagin could induce cell apoptosis through the intrinsic, mitochondrion-dependent apoptosis pathway via the aggregation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential ( m) in FOB1.19 and U2OS osteosarcoma cells [12]
To explore the potential effect of cinobufagin on uveal melanoma cells, a colony formation assay was used to determine the inhibitory effect of cinobufagin
Summary
Uveal melanoma (UM) represents the most frequently occurring primary intraocular malignant carcinoma in adults, with an annual incidence rate of 5.1 cases per million. Preliminary studies have demonstrated that CBG could suppress cell growth and induce apoptosis via the Notch pathway in osteosarcoma cells. The activation of Notch pathway could attenuate CBG-induced apoptosis [11]. Another report showed that cinobufagin could induce cell apoptosis through the intrinsic, mitochondrion-dependent apoptosis pathway via the aggregation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential ( m) in FOB1.19 and U2OS osteosarcoma cells [12]. In U266 human multiple myeloma cells, cinobufagin possibly exerted its antitumor effects via the activation of c-JUN N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38, mitogenactivated protein kinase (MAPK), and caspase-3 mediated through ROS [13]. Cinobufagin inhibited the cell growth and triggered apoptosis via the alternation of the expression of Bax and Bcl-2 in human breast cancer MCF-7 cells [10]. The antitumor activities and biochemical mechanism of cinobufagin in uveal melanoma are still elusive and need to be further elucidated
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