Combination of RGD compound and low-dose paclitaxel induces apoptosis in human glioblastoma cells

PLoS One. 2012;7(5):e37935. doi: 10.1371/journal.pone.0037935. Epub 2012 May 24.

Abstract

Background: 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 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 findings: Human 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.

Conclusions: This 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Caspases / metabolism
  • Cell Line, Tumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Integrin alphaVbeta3 / metabolism
  • Paclitaxel / administration & dosage
  • Paclitaxel / therapeutic use*
  • Peptides, Cyclic / administration & dosage
  • Peptides, Cyclic / therapeutic use*

Substances

  • Antineoplastic Agents, Phytogenic
  • Integrin alphaVbeta3
  • Peptides, Cyclic
  • cyclic arginine-glycine-aspartic acid peptide
  • Caspases
  • Paclitaxel