Selective Targeting of αvβ5 Integrin in HepG2 Cell Line by RGDechi15D Peptide

Abstract

Recently, the research community has become increasingly concerned with the receptor αvβ5, a member of the well-known integrin family. Different ongoing studies have evidenced that αvβ5 integrin regulates not only physiological processes but also a wide array of pathological events, suggesting the receptor as a valuable biomarker to specifically target for therapeutic/diagnostic purposes. Remarkably, in some tumors the involvement of the receptor in cell proliferation, tumor dissemination and angiogenesis is well-documented. In this scenario, the availability of a selective αvβ5 antagonist without ‘off-target’ protein effects may improve survival rate in patients with highly aggressive tumors, such as hepatocellular carcinoma. We recently reported a cyclic peptide, RGDechi15D, obtained by structure-activity studies. To our knowledge it represents the first peptide-based molecule reported in the literature able to specifically bind αvβ5 integrin and not cross react with αvβ3. Here we demonstrated the ability of the peptide to diminish both adhesion and invasion of HepG2 cells, an in vitro model system for hepatocellular carcinoma, to reduce the cell proliferation through an apoptotic process, and to interfere with the PI3K pathway. The peptide, also decreases the formation of new vessels in endothelial cells. Taken together these results indicate that the peptide can be considered a promising molecule with properties suited to be assessed in the future for its validation as a selective therapeutic/diagnostic weapon in hepatocarcinoma.

Integrins in human hepatocellular carcinoma tumorigenesis and therapy

“…In addition, several preclinical trials have been ongoing in evaluating the therapeutic efficacy of integrin targeting in antitumor therapy. [49,[142][143][144][145][146] As integrins are expressed in various normal cells, their targeting should be critically evaluated for both acute and chronic toxicities.…”

“…Under normoxic and hypoxic conditions, T7 peptide inhibits endothelial cell proliferation, migration, and angiogenesis through the integrin α3β1 and αVβ3 pathways and promotes apoptosis of HCC endothelial cells. [ 142 ] Capasso et al [ 143 ] recently reported a cyclic peptide RGDechi15D that specifically binds to integrin αVβ5 and does not cross-react with integrin αVβ3. Here, they demonstrated that RGDechi15D can interfere with the PI3K pathway, inhibit HCC cell adhesion, proliferation, and invasion, and reduce HCC endothelial cell angiogenesis.…”

“…Preclinical [141] Raj-tspin Peptide Inhibit the integrin b1/FAK/AKT signaling pathway Preclinical [49] T7 peptide Peptide Inhibit the integrin a3b1 and aVb3 pathways Preclinical [142] RGDechi15D Peptide Bind to integrin aVb5 and interfere with the PI3K pathway Preclinical [143] GA Natural compound Downregulate the expression of integrin b1/ Rho family GTPase signaling pathway Preclinical [144] Cordycepin Natural compound Suppress integrin a3, a6, and b1/FAK signaling pathway Preclinical [145] Fucoidan Natural polysaccharide Suppress integrin aVb3/Src/E2F1 signaling pathway Preclinical [146] AKT: Protein kinase B; E2F1: E2F transcription factor 1; FAK: Focal adhesion kinase; FN1: Fibronectin 1; GA: Garcinia cambogia acid; HCC: Human hepatocellular carcinoma; PI3K: Phosphoinositide 3-kinase.…”

Peptide therapeutics in the management of metastatic cancers

“…RGDechi15D reduces cell adhesion, migration, invasion, angiogenesis and proliferation of cancer cells overexpressing α v β 5 . 91 …”

“…RGDechi15D reduces cell adhesion, migration, invasion, angiogenesis and proliferation of cancer cells overexpressing a v b 5 . 91 Recently, a peptide mediated imaging technique for glioblastoma cells was reported. Transformed cells in glioblastoma show high intracellular levels of reactive oxygen species (ROS) and various imaging probes target these high ROS levels.…”