Moroccan Naja haje Venom and its Peptides: In Vivo Toxicity and In Vitro Antiproliferative Effect on Hepatocellular Carcinoma HepG2 Cells

Snake venom, despite its toxicity, presents notable therapeutic potential by specifically targeting tumor cells to inhibit their proliferation or induce their apoptosis. However, with the global rise in hepatocellular carcinoma rates, new treatments are needed that move away from surgery and toxic chemotherapy. Research has revealed that snake venoms, particularly those of cobras, contain promising molecules for the treatment of cancer.

Our study evaluates the toxicity (LD₅₀) of the Moroccan cobra venom Naja haje as well as its fractions obtained by gel filtration fractionation. We also analyze their antiproliferative activity on HepG2 hepatocellular carcinoma cells. Cell viability was determined by MTT assay and the fractions that exhibited proliferation inhibitions of HepG2 cells were analyzed by mass spectrometry (LC-MS/MS).

Our results show that the LD₅₀ of Naja haje venom varies depending on the route of administration, 0.69, 0.79 and 0.90 µg/g by intracerebroventricular, intravenous and intraperitoneal routes, respectively. On the other hand, the fractions, notably 1, 2, 3, 7 and 8, demonstrate significant antiproliferative activity on the HepG2 cells in vitro, and this activity is enhanced at a concentration of 50 µg/mL, highlighting their therapeutic potential. LC-MS/MS analysis of the active fractions revealed a complex molecular composition, including cytotoxins, neurotoxins, cardiotoxins, and a diverse array of peptides.

Fractions 7 and 8 from Naja haje venom showed significant antiproliferative effects on HepG2 cells at 10 µg/mL, enhanced at 50 µg/mL.