LyeTx-Ib-PEG as a Potential Antitumor Agent in Cervical Cancer: Effects on HPV Oncogenes and Interaction with Cisplatin

Introduction: Cervical cancer (CC) is associated with persistent high-risk HPV infection, whose E6 and E7 oncoproteins inactivate tumor suppressors p53 and pRB. Cisplatin toxicity and tumor resistance reinforce the search for novel selective therapeutic agents. LyeTx-Ib-PEG, a synthetic peptide derived from Lycosa erythrognata venom, conjugated to polyethylene glycol (PEG), showed antimicrobial activity, but its antitumor effect in CC has yet to be investigated. Aims: To evaluate the antitumor activity of LyeTx-Ib-PEG in CC cell lines and its effects on apoptotic genes and HPV oncoproteins. Methods: Following IC₅₀ determination in HeLa (HPV18), SiHa, CaSki (HPV16), and HEK293 (non-tumorigenic) cell lines, we evaluated clonogenic capacity, LyeTx-Ib-PEG/Cisplatin interaction (isobolographic analysis), and gene expression (RT-qPCR) related to apoptosis (CASP3, CASP8, CASP9, BAX, BCL2, TP53 and RB1) and viral oncogenes (E6 and E7). Results: Peptide IC₅₀ values were 22.4 µM in HeLa, 14.3 µM in SiHa, 25.0 µM in CaSki, and 36.1 µM in HEK293. At IC₅₀, clonogenic survival decreased to 0.20 in SiHa (p < 0.0001), 0.67 in CaSki (p = 0.002), and 0.33 in HeLa (p < 0.0001). Apoptotic gene expression was modulated exclusively in the CaSki cell line, characterized by a 1.3-fold upregulation of CASP8 (p = 0.002) along with BAX and BCL2 modulation. E6 and E7 fold changes decreased to 0.35–0.55 relative to control. Synergy with cisplatin occurred in CaSki (1:3 and 3:1) and an additive effect at 1:1; in HeLa and SiHa, interaction varied from additive to antagonistic. Conclusion: LyeTx-Ib-PEG showed selective antitumor activity in cervical cancer cell lines, reducing clonogenic survival and E6/E7 expression, modulating apoptotic pathways in a cell line-dependent manner, and synergizing with cisplatin in CaSki. Altogether, these preliminary findings demonstrate the antitumor activity of LyeTx-Ib-PEG, highlighting its potential for the development of a novel therapeutic agent against CC.