Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds.

Abstract

Glioblastoma (GB), the most aggressive brain tumour, and mantle cell lymphoma (MCL), a rare but very aggressive type of lymphoma, are highly resistant to chemotherapy. GB and MCL chemotherapy gives very modest results, the vast majority of patients experience recurrent disease. To find out the new treatment modality for drug-resistant GB and MCL cells, combining of bradykinin (BK) antagonists with conventional temozolomide (TMZ) treatment, and screening of thiazolidinones derivatives were the main objectives of this work. As it was revealed here, BKM-570 was the lead compound among BK antagonists under investigation (IC50 was 3.3 μM) in human GB cells. It strongly suppressed extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation. BK antagonists did not decrease the viability of MCL cells, thus showing the cell-specific mode, while thiazolidinone derivatives, a novel group of promising anti-tumour compounds inhibited proliferation of MCL cells: IC₅₀ of ID 4526 and ID 4527 compounds were 0.27 μM and 0.16 μM, correspondingly. However, single agents are often not effective in clinic due to activation of collateral pathways in tumour cells. We demonstrated a strong synergistic effect after combinatorial treatment by BKM-570 together with TMZ that drastically increased cytotoxic action of this drug in rat and human glioma cells. Small proportion of cells was still viable after such treatment that could be explained by presence of TMZ-resistant cells in the population. It is possible to expect that the combined therapy aimed simultaneously at different elements of tumourigenesis will be more effective with lower drug concentrations than the first-line drug temozolomide used alone in clinics.

• Authors: Stanislav Avdieiev, Lajos Gera, Dmytro Havrylyuk, Robert S Hodges, Roman Lesyk, Vincent Ribrag, Yegor Vassetzky, Vadym Kavsan
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 15 Pg. 3815-23 (Aug 01 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 25012567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• BKM-570
• Thiazolidines
• Tyrosine
• Dacarbazine
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Bradykinin
• Temozolomide

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Bradykinin (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dacarbazine (analogs & derivatives, chemistry, pharmacology)
• HEK293 Cells
• Humans
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Temozolomide
• Thiazolidines (chemical synthesis, chemistry, pharmacology)
• Tyrosine (analogs & derivatives, chemistry, pharmacology)