Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal antitumor agents in combination to its low toxicity. On the other hand, flavonoids are a wide family of polyphenolic compounds synthesized by plants that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, a exhaustive study of the mechanisms of action of two oxidovanadium(IV) complexes with the flavonoids: silibinin Na₂[VO(silibinin)₂2]·6H₂O (VOsil) and chrysin [VO(chrysin)₂EtOH]₂(VOchrys) on human colon adenocarcinoma derived cell line HT-29. The complexes inhibited the cell viability of colon adenocarcinoma cells in a dose dependent manner with a greater potency than that the free ligands and free metal, demonstrating the benefit of complexation. The decrease of the ratio of the amount of reduced glutathione to the amount of oxidized glutathione were involved in the deleterious effects of both complexes. Besides, VOchrys caused cell cycle arrest in G2/M phase while VOsil activated caspase 3 and triggering the cells directly to apoptosis. Moreover, VOsil diminished the NF-kB activation via increasing the sensitivity of cells to apoptosis. On the other hand, VOsil inhibited the topoisomerase IB activity concluding that this is important target involved in the anticancer vanadium effects. As a whole, the results presented herein demonstrate that VOsil has a stronger deleterious action than VOchrys on HT-29 cells, whereby suggesting that Vosil is the potentially best candidate for future use in alternative anti-tumor treatments.

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The ability of oxindolimine copper(II) and zinc(II) complexes, known to have antitumor activity, to inhibit human topoisomerase IB has been tested through enzymatic kinetic assays and molecular docking simulations. These copper and zinc compounds are able to inhibit remarkably the cleavage reaction and only partially the religation step, the copper compound being more efficient than the zinc one. A complete inhibition activity of the cleavage is only obtained when the enzyme is pre-incubated with the compound, the inhibition being irreversible and reversible for the copper and zinc compounds, respectively. The relative stability of such complexes was estimated by competitive equilibria with human serum albumin (HSA), monitored by CD spectroscopy. The copper species shows a log KCuL = 17.2, while the analogous zinc complex exhibits a log KZnL = 7.2. Molecular docking simulation studies show that the almost square planar geometry of the copper compound allows a direct coordination of the metal with two amino acids (Glu492, Asp563) of the enzyme at variance of the zinc compound which has a more tetrahedral geometry. Altogether, the data indicate that the different coordination geometry achieved by the two transition metal ions has an important role in modulating their efficiency as topoisomerase I inhibitors.

The different steps of the topoisomerase I catalytic cycle have been analyzed in the presence of the plant alkaloid thaspine (1- (2-(Dimethylamino)ethyl)-3,8-dimethoxychromeno[5,4,3-cde]chromene-5,10-dione), known to induce apoptosis in colon carcinoma cells. The experiments indicate that thaspine inhibits both the cleavage and the religation steps of the enzyme reaction. The inhibition is reversible and the effect is enhanced upon pre-incubation. Molecular docking simulations of thaspine over topoisomerase I, in the presence or absence of the DNA substrate, show that thaspine, when interacting with the enzyme alone in the closed or in the open state, can bind in proximity of the active residues preventing the cleavage reaction, whilst when docked with the enzyme-DNA cleavable complex intercalates between the DNA bases in a way similar to that found for camptothecin, explaining its religation inhibition. These results unequivocally demonstrate that thaspine targets human topoisomerase I .

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