Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells

Abstract

Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 μg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors’ knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom.

Therapeutic, chemo-sensitizing, protective effects of natural products against cancerous cells: Preclinical and clinical studies

“…Researchers have long been interested in using jellyfish venom to discover and create new anticancer drugs. According to Tawfik et al (2021) jellyfish venom is a rich source of bioactive proteins and peptides with a variety of biological activities, such as antioxidant, antibacterial, and anticancer properties. Nematocysts, which are specialized venomcontaining capsules found mostly in the tentacles of jellyfish, are the principal container for the venom of jellyfish.…”

“…Numerous investigations have unequivocally demonstrated the connection between jellyfish venom's capacity to cause oxidative stress and its activation of cancer cell death (Tawfik et al, 2021;De Domenico et al, 2023). The cytotoxicity of jellyfish venom, such as that of Pelagia noctiluca against colon cancer cells and Cassiopea andromeda against breast cancer cells, is attributed to the production of reactive oxygen species (ROS), the stimulation of lipid peroxidation, and damage to mitochondria (Ayed et al, 2011).…”

Redox Active Molecules in Cancer Treatments

“…They present antioxidative or targeted oxidative effects of miscellaneous small-molecular-weight compounds or proteins against a variety of cancer types: An endogenous compound—melatonin [ 2 ]. Natural plant compounds (naringenin [ 3 ], papaverine [ 4 ], polyphenols isolated from Myrciaria trunciflora [ 5 ] or Anneslea fragrans [ 6 ], and seed-derived peptides [ 7 ]), natural compounds also found in animals (melatonin [ 2 , 8 ]), and peptides as well as proteins from Jellyfish venom [ 9 ]. Synthetic compounds, i.e., alkyl thiols [ 10 ], dimethyl sulfoxide [ 11 ], metformin and S63845 [ 12 ], the ruthenium complex [Ru(Phen) 3 ] 2+ [ 13 ], and copper-based compounds—Casiopeinas [ 14 ].…”

“…Natural plant compounds (naringenin [ 3 ], papaverine [ 4 ], polyphenols isolated from Myrciaria trunciflora [ 5 ] or Anneslea fragrans [ 6 ], and seed-derived peptides [ 7 ]), natural compounds also found in animals (melatonin [ 2 , 8 ]), and peptides as well as proteins from Jellyfish venom [ 9 ].…”

“…Most studies examined the effect of the tested compounds on cancer cell viability/proliferation assays [ 2 , 3 , 4 , 6 , 11 , 12 ] and/or analyses of reactive oxygen species concentrations [ 2 , 3 , 6 , 11 , 15 , 16 ]. Some other studies used in vitro assays such as cell cycle analyses [ 2 , 3 , 4 , 9 ], DNA fragmentation assays [ 3 , 9 ], analyses of the expression of apoptosis-related proteins and/or genes [ 9 , 11 , 12 ], etc. The two included studies are based on the application of state-of-the-art chemoinformatic analysis and modeling approaches—molecular docking and molecular dynamics [ 7 , 18 ].…”