Deciphering the effect of an oxovanadium(iv) complex with the flavonoid chrysin (VOChrys) on intracellular cell signalling pathways in an osteosarcoma cell line

Abstract

Vanadium complexes were studied during recent years and considered as a representative of a new class of non-platinum metal antitumor agents in combination with their low toxicity. However, a few challenges still remain in the discovery of new molecular targets for these novel metal-based drugs. The study of cell signaling pathways related to vanadium drugs, which is highly critical for identifying specific targets that play an important role in the antitumor activity of vanadium compounds, is scarce. This research deals with the alterations in intracellular signaling pathways promoted by an oxovanadium(IV) complex with the flavonoid chrysin [VO(chrysin)₂EtOH]₂ (VOChrys) in a human osteosarcoma cell line (MG-63). Herein we report for the first time the effect of [VO(chrysin)₂EtOH]₂ on the relative abundance of 224 proteins, which are involved in the most common intracellular pathways. Besides, full-length human recombinant (FAK and AKT1) kinases are produced using an in situ IVTT system and then we have evaluated the variation of relative tyrosine-phosphorylation levels caused by the [VO(chrysin)₂EtOH]₂ compound. The results of the differential protein expression levels reveal that several proteins such as PKB/AKT, PAK, DAPK, Cdk 4, 6 and 7, FADD, AP2, NAK, and JNK, among others, were altered. Moreover, cell signaling pathways related to the PTK2B, FAK, PKC families suggests an important role associated with the antitumor activity of [VO(chrysin)₂EtOH]₂ was demonstrated. Finally, the effect of this compound on in situ expressed FAK and AKT1 is validated by determining the phosphorylation level, which decreased in the former and increased in the latter.