Amir Vazirizadeh

Background: Globally, hepatocellular carcinoma (HCC) is the 3rd leading reason for mortality associated with cancer and the 6th most widespread malignant tumor. Objectives: This study aims to investigate selective toxicity of venom fractions of Pseudosynanceia melanostigma, commonly known as stonefish, on hepatocytes and mitochondria obtained from diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC). Methods: Different dilutions of extracted fractions from crude stonefish venom were treated on hepatocytes and mitochondria isolated from a rat model of hepatocellular carcinoma induced by diethylnitrosamine (DEN). In response to stonefish venom fractions, mitochondrial related parameters including generation of reactive oxygen species(ROS),mitochondrialmembrane potential (MMP) collapse, mitochondrial swelling, cytochrome c release, activation of caspase 3, and induction of apoptosiswere investigated. Results: Our results demonstrate that for the first time, fraction 3 of Pseudosynanceia melanostigma treatment on cancerous mitochondria had a significant accumulation of reactive oxygen species (ROS). In addition, mitochondrial membrane potential (MMP) disruption, mitochondrial swelling, and cytochrome c release increased. Moreover, fraction 3 induced selective toxicity only in cancerous hepatocytes from the HCC but not those from healthy cells. Additional research also determined a significant increase in activation of caspase 3 and induction of apoptosis. Conclusions: In conclusion, this study provides evidence that fraction 3 of Pseudosynanceia melanostigma venom selectively induces apoptosis in cancerous hepatocytes from HCC through a ROS-mediated mitochondrial pathway.