Polyoxidovanadates [MoVIVV9O28]5- and [H2PtIVVV9O28]5- interact with CHO cell plasma membrane lipids causing aggregation and activation of a G protein-coupled receptor

Abstract

Mono substituted heteropolyoxidovanadates, when compared to effects of a corresponding isopolyoxidovanadate (POV), were found to be more effective initiators of signal transduction by a G protein-coupled receptor (GPCR), specifically the luteinizing hormone receptor (LHR). Here we report that LHRs signal productively when CHO cells expressing the receptor are treated with two heteropolyoxidovanadates PtIV in monoplatino(IV)nonavanadate(V) ([H2PtVIVV9O28]5-, V9Pt), and MoIV in monomolybdo(VI)nonavanadate(V) (Mo[VIVV9O28]5-, V9Mo). Both substituted decavanadate derivatives were more effective than decavanadate which is more charged, has greater stability and forms the [V10O28]6- anion (V10) in cell culture medium at pH 7.4. For viable CHO cells expressing 10 k or 32 k LHR/cell and treated with 11 μM V9Pt and 13 μM V9Mo, mono substituted heteropolyoxidovanadates significantly decreased the packing of plasma membrane lipids for about 1 h. This brief change in membrane structure was accompanied by increased aggregation of LHR and cell signaling as indicated by increased intracellular levels of cAMP. More pronounced changes in lipid packing and LHR signaling were associated with short acting heteropolyoxidovanadates than with the more stable V10. When LHR was overexpressed, V9Pt and V9Mo had little or no effect on membrane lipid packing or receptor aggregation and the LHR was constitutively activated as indicated by elevated intracellular cAMP levels. Speciation of V9Pt and V9Mo in H2O and cell medium was monitored using 51V NMR spectroscopy and confirmed that V9Pt and V9Mo had greater effects on CHO cells despite decomposing more rapidly in the cell growth medium. Thus, under conditions that promote CHO cell growth, V9Pt and V9Mo, despite their smaller molecular charge and their reduced stability, favor LHR signaling over that induced by V10. Importantly, under the same experimental conditions, CHO cells treated with V9Pt and V9Mo do not exhibit as strong toxic effects observed for cells treated with the longer lived V10. In summary, unlike the longer lived V10 which is more growth inhibitory to cells, monosubstituted heteropolyoxidovanadates are more effective in transiently initiating signaling by a G protein-coupled receptor but, because of rapid hydrolysis, inhibit cell growth less.

Substitution Kinetics, Albumin and Transferrin Affinities, and Hypoxia All Affect the Biological Activities of Anticancer Vanadium(V) Complexes

“…no. A8763) contained traces of fatty acids that are likely to be involved in the binding and stabilization of 1 and other hydrophobic small-molecule drugs. ,, Fatty acid content in HSA will change its affinities for V­(V) complexes, but there is no dispute that HSA binds complex 1 .…”

“…A wide range of biological activities, including anticancer, antimicrobial, antidiabetic, and tissue-regenerating properties, have been reported for structurally diverse V­(V/IV) complexes. − This diversity also allows a wide range of cancers that can be effected and potentially treated by these compounds. ,, Although the active species have rarely been identified, the effects of a significant number of complexes have been attributed to their decomposition in biological environments with the formation of V­(V) or V­(IV) oxido species, ,− which can act as potent phosphatase inhibitors. ,− Vanadate is known to inhibit all phosphorylase enzymes, and the inhibition of protein tyrosine phosphatases is particularly noteworthy considering their roles in signal transduction and regulation. − In addition, vanadate in the presence of hydrogen peroxide can form peroxido vanadates or other vanadium species involved in the reactive oxygen species (ROS)-related regulation of cell signaling. ,, A promising recent application is the use of inorganic V­(V/IV) salts and V­(V) complexes with organic ligands as potentiators of oncolytic viruses, − which are used for immunotherapy of advanced cancers. , …”

In Vitro, Oral Acute, and Repeated 28-Day Oral Dose Toxicity of a Mixed-Valence Polyoxovanadate Cluster

“…Moreover, POVs trigger many biochemical effects such as lipoperoxidation and oxidative stress, affecting metabolic pathways and cell cycle arrest. It interferes with ions transport systems and apoptosis, induces cell morphology changes, inhibits phosphorylases and redox enzymes, and activates or deactivates cell signaling [ 11 , 12 , 13 ]. Regarding its future clinical use, POV’s toxic effects on various biological systems remain a topic in need of more experimental data.…”

“…It also has effects as an antidiabetic and anticancer agent [ 23 ]. Recently, the transition-metal-monosubstituted decavanadates V 9 Mo and V 9 Pt were found to be effective in inhibiting the growth of Mycobacterium smegmatis [ 24 ] and Chinese Hamster Ovary (CHO) cells [ 12 ]. In both studies, the V 10 cluster was reported to be a more effective growth inhibitor; however, in bacteria, the cluster is bound more tightly and hence more cell associated than in the mammalian system, where V 9 Mo and V 9 Pt are readily washed off [ 12 , 24 ].…”