Abstract
PurposeSince 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.MethodsDNA 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.ResultsA 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.ConclusionThe investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.
Highlights
Developing new anti-cancer targets, especially against resistant tumors, is very challenging in cancer research (Kelland 2007)
The following microscopic photos visualize the effect of WQF 044 on the Nalm6 cells after 72 h of incubation
The analysis revealed a downregulation of the anti-apoptotic Bcl-2 by 18-fold and a 5-times upregulation of the Bcl-2-associated X protein (BAX) that is pro-apoptotic (Table 2) (Edlich 2018; Garner et al 2017)
Summary
Developing new anti-cancer targets, especially against resistant tumors, is very challenging in cancer research (Kelland 2007). The metal-free salan ligand THG 1213 (Scheme 1, bottom right) was much more active than the corresponding Mo-complexes (Dragoun et al 2018). Another striking observation was that the corresponding salen ligand THG 1212 (Scheme 1, bottom left) was inactive (Dragoun et al 2018). With this in mind, we decided to investigate the metal-free salalen ligand WQF 044
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