Abstract
According to the latest World Health Organization report, the incidence of brain tumor constitutes 1.8% of all cancer cases lower than other cancers (e.g., colorectal cancer, 9.2%; breast cancer, 25.2%); however, the final mortality close to 100% is firmly in the top 10 cancers. Currently, the standard therapeutic strategies for GBM include palliative care, radiation therapy, and surgery in combination with anti-cancer drugs. However, this malignant brain tumor is well known for its highly invasive behavior and typically responds poorly to conventional cytotoxic therapy. Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma multiforme (GBM) cells, and can be further induced by chemical or bio-mechanical stress. As a primary receptor of extracellular matrix adhesion molecules, integrin-αvβ3 acts as a crucial transducer to regulate cell signaling to die. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-αvβ3, and potential 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), to human GBM U87MG cells with the combination of low-dose Paclitaxel (PTX) pre-treatment to examine augmentation of therapeutic activity for RGD peptide-induced apoptosis. The docking simulation represented that both c(RGDyK) peptide and E[c(RGDyK)]2 peptide had better avidity and specificity to integrin-αvβ3 attachment (Ligscore 296.04 vs. 245.89). Human GBM 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 pretreated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 genes 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. This study proposes a novel method of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve the efficiency of human GBM treatment.