Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma Cells

Abstract

BackgroundIntegrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-αvβ3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK)) and bi-cyclic RGD (E[c(RGDyK)]2) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis.Principal FindingsHuman glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvβ3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK)]2 peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells.ConclusionsThis study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment.

Internalisation of RGD-Engineered Extracellular Vesicles by Glioblastoma Cells

“…Similarly to our data, several studies have revealed that RGD-conjugated drugs have more significant curative effects on GBM cells when compared to unmodified compounds [ 44 , 45 , 46 ]. Furthermore, Xin and co-authors demonstrated that exosomes functionalised with RGD had favourable gastric-tumour-targeting properties [ 47 ].…”

Epithelial Membrane Protein-2 (EMP2) Activates Src Protein and Is a Novel Therapeutic Target for Glioblastoma

“…As ␣v␤3 integrin is thought to be important for GBM progression, invasion, and survival, inactivation or suppression of this integrin may be sufficient to induce cell death (45). Consistent with the observed cytotoxicity of anti-EMP2 antibodies, downregulation of ␣v␤3 integrin by tumistatin or RGD peptides has been shown to induce apoptosis (46,47). In the case of tumistatin, apoptosis is induced via dampening of AKT signaling, and whether anti-EMP2 therapy has a similar effect on AKT signaling is currently being studied by our group.…”

RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis

“…Changes in integrin expression in response to chemotherapy can be exploited to increase response to anti-integrin therapeutics [175]. However, changes in expression could also render a targeted therapeutic ineffective therefore incorporation of an integrin antagonist into existing or novel drug combinations will require prior assessment of their effects on integrin expression at the preclinical stage.…”