Persian Gulf Stonefish (Pseudosynanceia melanostigma) Venom Fractions Selectively Induce Apoptosis on Cancerous Hepatocytes from Hepatocellular Carcinoma Through ROS-Mediated Mitochondrial Pathway

Abstract
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), mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, cytochrome c release, activation of caspase 3, and induction of apoptosis were 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.
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