Antitumor efficacy, pharmacokinetic and biodistribution studies of the anticancer peptide CIGB‐552 in mouse models

Abstract

Accumulation of the COMMD1 protein as a druggable pharmacology event to target cancer cells has not been evaluated so far in cancer animal models. We have previously demonstrated that a second-generation peptide, with cell-penetrating capacity, termed CIGB-552, was able to induce apoptosis mediated by stabilization of COMMD1. Here, we explore the antitumor effect by subcutaneous administration of CIGB-552 in a therapeutic schedule. Outstandingly, a significant delay of tumor growth was observed at 0.2 and 0.7 mg/kg (p < 0.01) or 1.4 mg/kg (p < 0.001) after CIGB-552 administration in both syngeneic murine tumors and patient-derived xenograft models. Furthermore, we evidenced that (131)I-CIGB-552 peptide was actually accumulated in the tumors after administration by subcutaneous route. A typical serine-proteases degradation pattern for CIGB-552 in BALB/c mice serum was identified. Further, biological characterization of the main metabolites of the peptide CIGB-552 suggests that the cell-penetrating capacity plays an important role in the cytotoxic activity. This report is the first in describing the antitumor effect induced by systemic administration of a peptide that targets COMMD1 for stabilization. Moreover, our data reinforce the perspectives of CIGB-552 for cancer targeted therapy.

Comparative analysis reveals amino acids critical for anticancer activity of peptide CIGB-552

“…In order to produce a more stable compound, modifications in the primary structure of L2 have been made resulting in a new generation of synthetic peptide: CIGB‐552. Properties already described for L2, regarding its ability to reduce tumor volume and produce cytotoxic effect in tumor cell lines, are retained by CIGB‐552 . Moreover, we have shown that CIGB‐552 stabilized COMMD1 levels, a protein involved in copper homeostasis, sodium transport, and the NF‐κB signaling pathway .…”

“…Previous results obtained for three CIGB‐552 degradation derived metabolites (referred to as 5, 1a and 3) indicated that differences in their sequence may affect their functionality . However, theoretical prediction of their cell penetrating capacity estimated by two different servers CPPpred and C2pred showed no differences on the probability of CIGB‐552 and its derived metabolites to be considered as cell‐penetrating peptides (CPPs) (Supplementary Table 1).…”

“…When exposed to BALB/c mice serum, CIGB-552 shows a typical serineprotease degradation pattern from which several metabolites are derived [9]. Three of these metabolites are metabolite 5, 1a, and 3 whose first characterization showed a decrease in their cellpenetrating capacity in NCI-H460 and HT-29 cell lines when compared to CIGB-552 [9]. Furthermore, the IC 50 (half maximal inhibitory concentration) values obtained for these metabolites in both cell lines were higher than those observed for CIGB-552 [9].…”

Efficacy studies of Sclerotium rolfsii lectin on breast cancer using NOD SCID mouse model

“…The tumor volume at day n (TVn) was calculated as TV (mm 3 ) = ( L − W 2)/2. The relative tumor volume at day n (RTVn) versus day 0 was expressed according to the formula: RTVn = TVn/TV 0 . Regression of tumor T/C (%) in treated versus control mice was calculated using: T/C (%) = (mean RTV of treated/control group) × 100.…”

Comparative proteomics analysis of the antitumor effect of CIGB-552 peptide in HT-29 colon adenocarcinoma cells

“…Among peptides, L-2 displayed the strongest in vitro cytotoxicity in human and mouse cancer cell lines [4]. The L-2 peptide primary structure was further modified to improve its activity and specificity yielding the second generation peptide CIGB-552 [5,6].…”