A Novel Platinum-Maurocalcine Conjugate Induces Apoptosis of Human Glioblastoma Cells by Acting through the ROS-ERK/AKT-p53 Pathway.

Abstract

Glioblastoma multiforme (GBM) is a highly malignant and aggressive primary brain tumor. In spite of an arsenal of therapeutic interventions, the prognosis of glioblastoma remains very poor. Cisplatin-based therapy is one of the most important chemotherapy treatments for GBM, although its efficacy is limited by drug resistance and undesirable side effects. In the present study, we designed a chimera molecule containing the platinum binding moiety MBL-III-7 (1) attached N-terminal to the sequence of d-maurocalcine (D-MCa), a protease-resistant and highly efficient cell-penetrating peptide (CPP) derived from the Tunisian chactid scorpion toxin, L-MCa. The concept behind this design is that MCa, through its cell retention properties, should reduce cell expulsion of the platinum complex and increase its efficiency. The anti-cancer properties of the synthesized platinum analogue Pt-MBL-III_7-D_MCa (Pt-1-DMCa) were assessed in human glioblastoma cells (U87) by assaying cell viability and apoptosis. The new molecule exhibited enhanced anti-cancer efficacy compared to cisplatin, especially at low doses. By inducing intracellular oxidative stress, Pt-1-DMCa potentiated platinum-induced DNA damage and led to enhanced p53 phosphorylation, followed by increased activation of both mitochondrial and death receptor pathways. Decreased phosphorylated AKT and ERK levels were associated with the apoptosis induced by the novel synthesized cisplatin analogue. Our results suggested that a chimera between platinum and a maurocalcine-derived CPP is a highly successful anti-cancer compound that works by targeting the intracellular redox system. Pt-1-DMCa is an interesting candidate for a preclinical assessment of platinum-based therapy in GBM treatments and possibly other cancer types.

• Authors: Sonia Aroui, Lucie Dardevet, Wafa Ben Ajmia, Madryssa de Boisvilliers, Florian Perrin, Amel Laajimi, Ahcène Boumendjel, Abderraouf Kenani, Jean Marc Muller, Michel De Waard
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 12 Issue 12 Pg. 4336-48 (Dec 07 2015) ISSN: 1543-8392 [Electronic] United States
• PMID: 26465677 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Reactive Oxygen Species
• Scorpion Venoms
• TP53 protein, human
• Tumor Suppressor Protein p53
• maurocalcine
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Glioblastoma (drug therapy, metabolism)
• Humans
• MAP Kinase Signaling System (drug effects)
• Organoplatinum Compounds (pharmacology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Scorpion Venoms (pharmacology)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53