ABSTRACT
The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(H2O)](H2O)2 (I) and [(acr)H][VO(nta)(H2O)](H2O)2 (II), were determined. Additionally, the cytotoxic effects of four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts-1,10-phenanthrolinium, [(phen)H][VO(nta)(H2O)](H2O)0.5 (III), 2,2'-bipyridinium [(bpy)H][VO(nta)(H2O)](H2O) (IV), and two newly synthesized compounds (I) and (II)-were evaluated against prostate cancer (PC3) and breast cancer (MCF-7) cells. All the compounds exhibited strong cytotoxic effects on cancer cells and normal cells (HaCaT human keratinocytes). The structure-activity relationship analysis revealed that the number and arrangement of conjugated aromatic rings in the counterion had an impact on the antitumor effect. The compound (III), the 1,10-phenanthrolinium analogue, exhibited the greatest activity, whereas the acridinium salt (II), with a different arrangement of three conjugated aromatic rings, showed the lowest toxicity. The increased concentrations of the compounds resulted in alterations to the cell cycle distribution with different effects in MCF-7 and PC3 cells. In MCF-7 cells, compounds I and II were observed to block the G2/M phase, while compounds III and IV were found to arrest the cell cycle in the G0/G1 phase. In PC3 cells, all compounds increased the rates of cells in the G0/G1 phase.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Male , Female , MCF-7 Cells , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Nitrilotriacetic Acid/chemistry , Nitrilotriacetic Acid/analogs & derivatives , Structure-Activity Relationship , Cell Line, Tumor , Cell Proliferation/drug effects , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Vanadium/chemistry , Vanadium/pharmacology , PC-3 Cells , Cell Cycle/drug effects , Molecular Structure , Salts/chemistry , Salts/pharmacology , Cell Survival/drug effects , Apoptosis/drug effectsABSTRACT
In this article, the implications of binding competition of vanadates(V) with dodecyl sulfates for bovine serum albumin on cytotoxicity of vanadium(V) species against prostate cancer cells have been investigated. The pH- and SDS-dependent vanadate(V)-BSA interactions were observed. At pH 5, there is only one site capable of binding ten vanadates(V) ions (logK(ITC)1 = 4.96 ± 0.06; ΔH(ITC)1 = -1.04 ± 0.03 kcal mol-1), whereas at pH 7 two distinctive binding sites on protein were found, saturated with two and seven V(V) ions, respectively (logK(ITC)1 = 6.11 ± 0.06; ΔH(ITC)1 = 0.78 ± 0.12 kcal mol-1; logK(ITC)2 = 4.80 ± 0.02; ΔH(ITC)2 = - 4.95 ± 0.14 kcal mol-1). SDS influences the stoichiometry and the stability of the resulting V(V)-BSA complexes. Finally, the cytotoxicity of vanadates(V) against prostate cancer cells (PC3 line) was examined in the presence and absence of SDS in the culture medium. In the case of a 24-h incubation with 100 µM vanadate(V), a ca. 20 % reduction in viability of PC3 cells was observed in the presence of SDS. However, in other considered cases (various concentrations and time of incubation) SDS does not affect the dose-dependent action of vanadates(V) on the investigated prostate cancer cells.
Subject(s)
Prostatic Neoplasms , Vanadates , Humans , Male , Vanadates/pharmacology , Vanadates/chemistry , Vanadium/pharmacology , Vanadium/metabolism , Serum Albumin, Bovine , Cell Culture TechniquesABSTRACT
The binding interactions of bovine serum albumin (BSA) with tetraphenylborate ions ([B(Ph)4]-) have been investigated by a set of experimental methods (isothermal titration calorimetry, steady-state fluorescence spectroscopy, differential scanning calorimetry and circular dichroism spectroscopy) and molecular dynamics-based computational approaches. Two sets of structurally distinctive binding sites in BSA were found under the experimental conditions (10 mM cacodylate buffer, pH 7, 298.15 K). The obtained results, supported by the competitive interactions experiments of SDS with [B(Ph)4]- for BSA, enabled us to find the potential binding sites in BSA. The first site is located in the subdomain I A of the protein and binds two [B(Ph)4]- ions (logK(ITC)1 = 7.09 ± 0.10; ΔG(ITC)1 = -9.67 ± 0.14 kcal mol-1; ΔH(ITC)1 = -3.14 ± 0.12 kcal mol-1; TΔS(ITC)1 = -6.53 kcal mol-1), whereas the second site is localized in the subdomain III A and binds five ions (logK(ITC)2 = 5.39 ± 0.06; ΔG(ITC)2 = -7.35 ± 0.09 kcal mol-1; ΔH(ITC)2 = 4.00 ± 0.14 kcal mol-1; TΔS(ITC)2 = 11.3 kcal mol-1). The formation of the {[B(Ph)4]-}-BSA complex results in an increase in the thermal stability of the alfa-helical content, correlating with the saturation of the particular BSA binding sites, thus hindering its thermal unfolding.
