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.
Original language | English |
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Pages (from-to) | 3815-3823 |
Number of pages | 9 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 22 |
Issue number | 15 |
DOIs | |
State | Published - Aug 1 2014 |
Bibliographical note
Funding Information:This work was supported in part by National Academy of Sciences of Ukraine in frames of the program ‘Fundamental basis of molecular and cell biotechnologies’, Project 294932 ‘COMBIOM’, Grants N2006 008196 from the Fondation de France and ERABL from the Institut National du Cancer de France (INCa). We acknowledge support from FEBS for the Collaborative Experimental Scholarship for Central and Eastern Europe to S.A. and the J. Stewart Endowed Chair in Peptide Chemistry to R.S.H.
Keywords
- Bradykinin antagonists
- Glioblastoma
- Mantle cell lymphoma
- Multitargeted complex therapy
- Thiazolidinones
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry