Study of Cinobufagin as a Promising Anticancer Agent in Uveal Melanoma Through Intrinsic Apoptosis Pathway

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.

Deltamethrin induces apoptosis in cerebrum neurons of quail via promoting endoplasmic reticulum stress and mitochondrial dysfunction

“…[64][65][66] When mitochondria undergo apoptosis, the expression of Bcl-2 will be inhibited. 67 Simultaneously, the permeability of the mitochondrial membrane changes, then AIF and Cyt C are released from the mitochondria into the cytoplasm. AIF can be transported into the nucleus and cause DNA fragmentation.…”

“…The release of ROS can cause oxidative stress in cells and it can trigger apoptosis through a variety of signaling pathways 64–66 . When mitochondria undergo apoptosis, the expression of Bcl‐2 will be inhibited 67 . Simultaneously, the permeability of the mitochondrial membrane changes, then AIF and Cyt C are released from the mitochondria into the cytoplasm.…”

ZNF667‐AS1, a positively regulating MEGF10, inhibits the progression of uveal melanoma by modulating cellular aggressiveness

“…Its promotion has been regarded as a prospective method for the inhibition of cancer development. [ 30 ] Bcl‐2 and Bax are crucial molecules in apoptosis. [ 31 ] Results showed that ZNF667‐AS1 increased the p53 and Bax expression, and decreased the expression of cyclin D1 and Bcl‐2.…”

Preparation, Characterization, and In Vitro Release of Curcumin-Loaded IRMOF-10 Nanoparticles and Investigation of Their Pro-Apoptotic Effects on Human Hepatoma HepG2 Cells

“…ROS can directly damage the integrity of the mitochondrial membrane by hyperpolarizing the mitochondrial membrane and releasing cytochrome c into the cytoplasm [53,54]. In addition, ROS can also damage mitochondrial DNA, which is related to the respiratory chain, thereby aggravating the production of ROS [55]. On the other hand, a large amount of ROS may also cause nuclear DNA damage [56], upregulate the expression of p53, block the cell cycle in the S phase, and activate the mitochondrial-dependent apoptotic pathway [36].…”