Sina M Hopff1, Qifang Wang2, Corazon Frias3, Marie Ahrweiler3, Nicola Wilke3, Nathalie Wilke3, Albrecht Berkessel2, Aram Prokop3,4,5. 1. Department of Pediatric Hematology/Oncology, Municipal Clinics of Cologne, Children's Hospital of the City Cologne, Amsterdamer Straße 59, 50735, Cologne, Germany. sina.hopff@uk-koeln.de. 2. Department of Chemistry, University of Cologne, Greinstraße 4, 50939, Cologne, Germany. 3. Department of Pediatric Hematology/Oncology, Municipal Clinics of Cologne, Children's Hospital of the City Cologne, Amsterdamer Straße 59, 50735, Cologne, Germany. 4. Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055, Schwerin, Germany. 5. Medical School Hamburg (MSH), University of Applied Sciences and Medical University, Am Kaiserkai 1, 20457, Hamburg, Germany.
Abstract
PURPOSE: Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044. METHODS: DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions. RESULTS: A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells. CONCLUSION: The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.
PURPOSE: Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044. METHODS: DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions. RESULTS: A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells. CONCLUSION: The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.
Authors: Rodrigo S Corrêa; Monize M da Silva; Angelica E Graminha; Cássio S Meira; Jamyle A F Dos Santos; Diogo R M Moreira; Milena B P Soares; Gustavo Von Poelhsitz; Eduardo E Castellano; Carlos Bloch; Marcia R Cominetti; Alzir A Batista Journal: J Inorg Biochem Date: 2016-01-02 Impact factor: 4.155
Authors: Kieron Dunleavy; Stefania Pittaluga; Margaret Shovlin; Seth M Steinberg; Diane Cole; Cliona Grant; Brigitte Widemann; Louis M Staudt; Elaine S Jaffe; Richard F Little; Wyndham H Wilson Journal: N Engl J Med Date: 2013-11-14 Impact factor: 91.245
Authors: Lei Bao; Fernanda Festa; Christopher S Freet; John P Lee; Iwona M Hirschler-Laszkiewicz; Shu-Jen Chen; Kerry A Keefer; Hong-Gang Wang; Andrew D Patterson; Joseph Y Cheung; Barbara A Miller Journal: Sci Rep Date: 2019-10-01 Impact factor: 4.379