title: 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.affiliation: Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, National Academy of Science of Ukraine, 150 Zabolotnogo Str., Kyiv 03680, Ukraine. Electronic address: stasavdieiev@gmail.com.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Avdieiev
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Lajos
authors.initials: L
authors.lastname: Gera
authors.affiliation: Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Str., Lviv 79010, Ukraine.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Havrylyuk
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hodges
authors.affiliation: Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Str., Lviv 79010, Ukraine.
authors.forename: Roman
authors.initials: R
authors.lastname: Lesyk
authors.affiliation: Gustave Roussy Institute, 39 Camille-Desmoulins Str., Villejuif 94805, France; INSERM U1009, The University of Paris-Sud 11, Gustave Roussy Institute, 39 Camille-Desmoulins Str., Villejuif 94805, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: CNRS UMR8126, The University of Paris-Sud 11, Gustave Roussy Institute, 39 Camille-Desmoulins Str., Villejuif 94805, France.
authors.forename: Yegor
authors.initials: Y
authors.lastname: Vassetzky
authors.affiliation: Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, National Academy of Science of Ukraine, 150 Zabolotnogo Str., Kyiv 03680, Ukraine.
authors.forename: Vadym
authors.initials: V
authors.lastname: Kavsan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001920:Bradykinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077204:Temozolomide; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D000970:Antineoplastic Agents; D001920:Bradykinin; D003606:Dacarbazine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide; D053778:Thiazolidines; D014443:Tyrosine; C506333:BKM-570; D005466:Fluorocarbons
keywords: Bradykinin antagonists; Glioblastoma; Mantle cell lymphoma; Multitargeted complex therapy; Thiazolidinones