High cytotoxicity of vanadium(IV) complexes with 1,10-phenanthroline and related ligands is due to decomposition in cell culture medium

Abstract

Cytotoxic effects of Metvan (cis-[VO(OSO)(Mephen)], where Mephen = 4,7-dimethyl-1,10-phenanthroline) and its analogues with 1,10-phenanthroline (phen) and 2,2'-bipyridine (bpy) ligands in cultured human lung cancer (A549) cells have been re-investigated in conjunction with reactivity of the V(IV) complexes in neutral aerated aqueous solutions and in cell culture medium. All the V(IV) complexes underwent rapid oxidation to the corresponding V(V) species (cis-[V(O)L]), followed by release of free ligands (shown by electrospray mass spectrometry). Decomposition of V(IV) complexes in cell culture medium within minutes at 310 K was confirmed by UV-Vis and EPR spectroscopies. High cytotoxicities (low μM or sub-μM IC range in 72 h assays) were observed for the phen and Mephen complexes, but they were not different from that of the corresponding free ligands, which confirmed that the original V(IV) complexes played no significant role in the observed biological activities. The cytotoxicities of the ligands were most likely due to their complexation of redox-active essential metal ions, such as Cu(II) and Fe(II), in the medium, and their increased cellular uptake, leading to oxidative stress-related cell death. These results emphasize the need to assess the stability of metal-based drugs under the conditions of biological assays, particularly when biologically active ligands, such as 1,10-phenanthroline and its derivatives, are used. These ligands have high systemic toxicities in vivo and their release in the GI tract and blood makes the complexes unsuitable for use as anti-cancer drugs.

Metal dyshomeostasis based biomarkers of lung cancer using human biofluids

“…On the other hand, some authors have reported the anticancer properties of vanadium and showed that complexes of these metals are the new metal-based drugs used in the treatment of several cancers, such us lung cancer 43 . Other authors have demonstrated the influence of vanadium compounds in the cytotoxicity of some ligands in human lung cancer cultured cells 44 .…”

Vanadium Compounds as PTP Inhibitors

“…However, it was also shown that the ligands themselves generate a similar toxicity profile in MTT assays of leukaemia cells [ 37 ]. Furthermore, it has now been shown that Metvan dissociates in cell culture medium to release vanadium and free 1,10-phenanthroline (phen) ligands [ 38 , 39 ]. Treatment with these phen ligands alone results in similar cytotoxicity in a lung cancer cell line (A549) compared to the whole Metvan complex.…”

“…These ligands can also complex with copper and iron in the media, leading to enhanced cellular uptake, where they increase ROS production, ultimately leading to cell death [ 40 ]. Systemic toxicity associated with phen ligand has also been demonstrated in vivo [ 38 , 41 ]. Therefore, vanadium compounds containing such ligands are unlikely to be suitable for therapeutic applications directed solely at PTP enzymes themselves.…”

Decavanadate Inhibits Mycobacterial Growth More Potently Than Other Oxovanadates

“…However, a wide range of activities have been reported depending on the protein, biological system or specific vanadium species (Crans, 2000 ; Crans et al, 2013 ; Correia et al, 2015 ; Postal et al, 2016 ). Recently, it has become clear that compound uptake is critical to the mode of action because many vanadium compounds are modified during the uptake process (Pessoa and Tomaz, 2010 ; Crans et al, 2011 ; Le et al, 2017 ; Levina et al, 2017a ). In the case of a large anion such as decavanadate, the question is simply whether the species is too large to enter through protein channels and thus must be taken up through endocytosis or passive transport mechanisms.…”