Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone
Introduction
Curcumin, an extract of turmuric, Curcuma longa L., has been used for centuries in a variety of pharmaceutical applications [1], [2], [3], including as a treatment for arthritis [4], as an anti-inflammatory agent [5], [6] and as an orally available treatment for diabetes [7]. Curcumin is well absorbed, both in vitro [8] and in vivo [9], and has an exceedingly low toxicity index [6], [10]. Administration of curcumin, 80 mg kg−1 day−1 by oral gavage for 21 days, reduced blood sugar, glycosylated hemoglobin and thiobarbituric reactive substances (a measure of oxidative stress) in liver and plasma in alloxan-induced diabetic albino rats [7]. The anti-diabetic potential of curcumin itself has also been shown by amelioration of kidney lesions associated commonly with streptozotocin (STZ)-induced diabetes in the rat [11] and decreased oxidative stress, including prevention of advanced glycosylation end products (AGEs) in diabetic rats [12]. The curcuminoids (1,7-diaryl-1,6-heptadiene-3,5-diones), of which curcumin is a naturally occurring phytochemical, are potent antioxidants [13], inhibiting lipid peroxidation [14], reducing oxidative damage in an Alzheimer transgenic mouse [15] and effectively scavenging superoxide, the hydroxyl radical and nitrogen dioxide [16], [17], among other reactive oxygen species (ROS) [17], [18]. They also readily bind to divalent metal ions, through keto-enol tautomerization of the β-diketonate moiety [14], [17], [18], [19].
A variety of metallocomplexes of curcumin have been previously synthesized and characterized, usually with biological studies in mind. These include a five-coordinate curcumin–gold complex, Au(cur)2Cl, in which curcuminate is bidentate [20]; its anti-arthritic properties were assessed in an adjuvant-induced rat polyarthritis model. Greatly reduced paw swelling was seen after 3 weeks of Au(cur)2Cl, 30 mg kg−1 day−1 by injection. Three manganese complexes, prepared by reaction of manganese acetate with curcumin or one of two related compounds, diacetylcurcumin and 4-(4-hydroxy-3-methoxy-phenyl)-1-[7-(4-hydroxy-3-methoxy-phenyl)-[1,4]diazepan-5-ylidene]but-3-en-2-one [21], were isolated, characterized and tested in vitro for antioxidant properties and superoxide dismutase activity, with IC50 values for the former in the range 6.3–26.3 μM, and for the latter 8.9–29.9 μM. All three were also tested in vivo for their potential as neuroprotective agents in vascular dementia; Mn(curcumin)(OAc) showed significant protective effects in a transient ischemia/reperfusion mouse model of neuronal damage [21]. Cu(II) complexes of curcumin and analogues have been synthesized and tested for anti-tumour effects, both in vivo and in vitro, with considerable success [22], [23]. Of a series of metal curcuminoids, the CuL2 complexes were most cytotoxic in cultured L929 cells [22], and also showed significant reduction in solid tumour volume in ascites tumour-bearing mice. Recently, syntheses of a series of 1,7-diarylheptanoids and their VO(IV), Co(II), Ni(II) and Cu(II) complexes were reported [23]. The Cu(II) coordination complexes of these ligands had IC50 values of 6.6–11.1 μM in Erlich ascites tumour cells [23].
Coordination complexes of vanadyl ion and peroxovanadate [24] are also of interest as candidate chemotherapeutic agents [25], [26], [27], [28], [29], [30]. Vanadium is an ubiquitous trace element (cellular concentrations ≅ 10−8 M in mammals), which is able to influence signal transduction cascades with extraordinary sensitivity at several regulatory points [31]. VO(IV) coordination complexes have been extensively investigated for their insulin mimetic or enhancing potential [32], [33], [34]. In particular, bis(maltolato)oxovanadium(IV) (BMOV) and bis(ethylmaltolato)oxovanadium(IV) (BEOV), VO(IV) complexes with maltol or ethylmaltol, both of which are approved food additives, have proven effective as anti-diabetic agents in a variety of animal models of diabetes mellitus [32], [34], [35]. Vanadium’s potential in vanadium-containing chemotherapeutic agents, and in anti-diabetic agents, may be linked to potent inhibition of protein tyrosine phosphatase enzymes [31], [36], [37]. Vanadium is also known to have both pro- and antioxidant properties, depending on dose and chelation [37], [38], [39], [40]. The combined effects of protein tyrosine phosphatase inhibition and antioxidant properties of vanadyl ion (for both) and curcumin (for the latter) present an ideal opportunity to test the potential of synergistic enhancement of ligand effects by combination with an appropriate metal ion [41].
Previous studies have explored the potential for complementarity in pharmacological potency when metal ions are complexed to functional ligands, e.g. in vanadyl biguanides [42], vanadyl complexes of thiazolidinediones [43] (both for insulin mimetic effect), and Au(I) and Cu(II) clotrimazole and ketoconazole as anti-parasitic infection drugs [44]. In this study, we synthesized a bis(ligand)oxovanadium(IV) complex, with the curcuminate anion as the ligand, in order to take advantage of the pharmacological properties of both curcumin and vanadyl, with potential complementary efficacy.
Section snippets
Chemicals and materials
All solvents (Sigma–Aldrich) and chemicals were reagent grade and used without further purification: vanadyl acetylacetonate, vanadyl sulfate trihydrate (Aldrich Chemical, Milwaukee, WI), carboxymethylcellulose, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) (Sigma, St. Louis, MO); curcumin (Sigma–Aldrich, Mississauga, ON). Water was deionized (Barnstead D8902 and D8904 cartridges) and distilled (Corning MP-1 Megapure Still) before use. The yields are for analytically pure
Results and discussion
Vanadyl curcumin was synthesized successfully from readily available substrates, vanadyl acetylacetonate and curcumin (1,7-bis[4-hydroxy-3-methyoxyphenyl]-1,6-heptadiene-3,5-dione) (Fig. 1). Curcumin has a strong tendency to lose hydroxyl and methoxy groups, which are replaced by protons, as evidenced in the LSIMS spectrum obtained (vide supra); however, the close fit of the elemental analysis indicates that essentially all of the product is in the bis(diferuloyl methane) form. A broad medium
Conclusion
Vanadyl curcumin was more effective in inhibiting smooth muscle cell growth, synoviocyte proliferation, and mouse lymphoma cell growth than was curcumin alone. Curcumin alone was effective as an inhibitor of smooth muscle cell growth at IC50 = 13 μM, which was more than four times the concentration of vanadyl curcumin (IC50 = 2.9 μM) required for similar effect. Vanadyl curcumin was also an efficient inhibitor of synoviocyte proliferation (IC50 = 4.4 μM), suggesting striking potential as a
Abbreviations
- VO(cur)2
vanadyl curcumin
- VO(acac)2
vanadyl acetylacetonate
- ROS
reactive oxygen species
- DMSO
dimethyl sulfoxide
- DMEM
Dulbecco’s modified Eagle’s medium
- FBS
fetal bovine serum
- RPMI-1640
(medium named after Roswell Park Memorial Institute)
- GI
gastrointestinal
- BMOV
bis(maltolato)oxovanadium (IV)
- BEOV
bis(ethylmaltolato)oxovanadium (IV)
- STZ
streptozotocin
- CMC
carboxymethylcellulose
- MTT
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide
- LSIMS
liquid secondary ion mass spectrometry
- EPR
electron paramagnetic resonance
- IC
Acknowledgments
This work was supported financially by the Canadian Institutes of Health Research (CIHR), and the Natural Sciences and Engineering Research Council (NSERC), both of Canada, as well as by Angiotech Pharmaceuticals, Inc. J.T. thanks Merck Company Foundation National Summer Student Research Programme. We thank Dr. Marco Melchior for useful discussions on the synthesis of vanadyl curcumin, Dr. Barry Liboiron for the EPR spectrum, Tim Storr for the magnetic susceptibility measurement and Mary
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