Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds |
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| Affiliation: | 1. Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, National Academy of Science of Ukraine, 150 Zabolotnogo Str., Kyiv 03680, Ukraine;2. Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA;3. Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Str., Lviv 79010, Ukraine;4. Gustave Roussy Institute, 39 Camille-Desmoulins Str., Villejuif 94805, France;5. INSERM U1009, The University of Paris-Sud 11, Gustave Roussy Institute, 39 Camille-Desmoulins Str., Villejuif 94805, France;6. CNRS UMR8126, The University of Paris-Sud 11, Gustave Roussy Institute, 39 Camille-Desmoulins Str., Villejuif 94805, France;1. Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (Formerly Faculty of Pharmacy), Jamia Hamdard, New Delhi, 110062, India;2. Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India;3. Department of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz University, P.O. Box- 173, Al-Kharj, Saudi Arabia;4. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India;2. Endocrinology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Sector 10, Jankipuram, Sitapur Road, Lucknow 226 031, India;3. Department of Surgery, CSM Medical University, Lucknow, India;4. Academy of Scientific & Innovative Research (AcSIR), New Delhi, India;1. Institut de Chimie Organique et Analytique, Université d’Orléans, UMR-CNRS 7311, BP 6759, rue de Chartres, 45067, Orléans Cedex 2, France;2. Equipe de Chimie Bioorganique & Analytique, URAC 22 Université Hassan II Mohammedia-Casablanca, BP 146, 28800, Mohammedia, Morocco;3. Laboratoire de Chimie Organique et Analytique, Université Sultan Moulay Slimane - Faculté des Sciences et Techniques, BP 523, 23000, Beni-Mellal, Morocco;4. Department of Physiology, Faculty of Medicine, Ege University, 35100, Bornova, Izmir, Turkey;5. Department of Biochemistry, Faculty of Pharmacy, Ege University, 35100, Bornova, Izmir, Turkey;6. Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy |
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| 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. |
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| Keywords: | Multitargeted complex therapy Glioblastoma Mantle cell lymphoma Bradykinin antagonists Thiazolidinones |
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