<i>In Vitro</i> Antitumor Activity of a Keggin Vanadium-Substituted Polyoxomolybdate and Its ctDNA Binding Properties

Qi, Wen; Qin, Ying; Qi, Yanfei; Guo, Li; Li, Juan

doi:https://doi.org/10.1155/2015/753751

Journal of Chemistry

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Research Article | Open Access

Volume 2015 | Article ID 753751 | https://doi.org/10.1155/2015/753751

In Vitro Antitumor Activity of a Keggin Vanadium-Substituted Polyoxomolybdate and Its ctDNA Binding Properties

Wen Qi,¹Ying Qin,²Yanfei Qi,¹Li Guo,¹and Juan Li¹

Academic Editor: Taohai Li

Received01 Aug 2014

Accepted26 Aug 2014

Published26 Mar 2015

Abstract

A Keggin vanadium-substituted polyoxomolybdate, K₅PMo₁₀V₂O₄₀ (PMo₁₀V₂), has been synthesized and it’s antitumor effect against Hela cells was investigated. The calf thymus DNA (ctDNA) binding ability of PMo₁₀V₂ was also evaluated by UV-Vis absorption spectra and fluorescence spectra. The identity and high purity of PMo₁₀V₂ was confirmed by elemental analysis and IR analysis. And the antitumor activity test of PMo₁₀V₂ was carried out on Hela cancer cells line by MTT assay. The results of MTT assay show that PMo₁₀V₂ significantly reduced the viability of Hela cells in a dose-dependent manner and exhibited stronger inhibitory activity against Hela cells at an IC₅₀ of 800 μg/mL, which is more effective than the positive control, 5-Fu . The results of the UV-Vis absorption spectra and fluorescence spectra indicated the groove or outside stacking binding between PMo₁₀V₂ and ctDNA. These results show that the antitumor activity of PMo₁₀V₂ may be caused by the interactions between DNA and PMo₁₀V₂.

1. Introduction

The current interest in polyoxometalates (POMs) keeps on increasing worldwide, not only because of their enormous structural variety, but also their potential applications in multitudinal fields such as catalysis, medicine, and functional materials [1, 2]. Especially, the medicinal properties of POMs have been a subject of interest in drug discovery. In the literature, POMs serve as a few kinds of inorganic medicinal candidates that have been documented to exhibit antiviral activities and antitumor activities [3–6]. For instance, the PM-8 polyoxometalate synthesized by Yamase and coworkers and that has been evaluated for in vivo and in vitro antitumor activities found to induce apoptotic cell death in human pancreatic cancer cells, AsPC-1, and possesses potent antitumor activity against human Co-4 colon, MX-1 breast, and lung cancer [7–10]. In addition, the group also proposed mechanism that a single electron reduction∖oxidation cycle of PM-8 in tumor cells could inhibit the ATP generation [11]. On the other hand, these compounds are less expensive than those of organic medicines, attracting great attention on the medicinal exploration. During the last 20 years, it has been established that the size, shape, and charge density of many polyoxoanions are strongly relative to their biological activities and toxicity [12, 13].

Cancer is difficult to treat and developing efficient antitumor medicines remain one of the most important goals of modern medicinal chemistry research [14]. Cancer starts due to prototype causative factors in a group of cells, leading to DNA damage, thus causing genetic mutations or chromosome structure, the number of different changes, which in turn leads to irreversible changes. DNA is very important genetic substance in any organism and a primary intracellular target for antitumor drugs. The interactions between DNA and small molecules can cause damage in cancer cells and lead to cell death [15]. In recent year the interaction of drugs with DNA and investigation of new effective DNA probes have been focused on the study of small molecular interacting with DNA [16]. POMs are seldom researched in the agents that directly interact with DNA, [17–20], which have shown the ability on inhibiting tumor growth by affecting the mitotic index, the synthesis of DNA, the activity of succinct hydrogenase, cytochrome oxidase, and acid phosphatase of tumor cells [21].

As a part of our ongoing antitumor drug discovery, a number of POMs have been synthesized and evaluated for their potential antitumor activities [22–25]. Herein, a Keggin vanadium-substituted polyoxomolybdate, K₅PMo₁₀V₂O₄₀ (PMo₁₀V₂), was prepared. The antitumor activity against Hela cells of PMo₁₀V₂ were investigated in vitro. The results indicate that PMo₁₀V₂ exhibits strong antitumor activity against the Hela cells, indicating that it is a potential antitumor candidate. The calf thymus DNA (ctDNA) binding ability of PMo₁₀V₂was also investigated, using UV-Vis absorption spectra and fluorescence quenching.

2. Experiment

2.1. General Procedures

All solvents and chemicals were used as obtained from commercial supplies. The ctDNA and ethidium bromide (EB) were purchased from Sigma Company. The solution of ctDNA was prepared by dissolving ctDNA in phosphate buffer solution at 4°C under intense stirring for more than 24 h to get a homogeneous solution. Solutions of ctDNA in 10 mM phosphate buffer solution (PBS, 10 mM) of pH 7.4 gave a ratio of UV absorbance at 260 nm and 280 nm; / was 1.82, indicating that the ctDNA was sufficiently free of protein and need no more further purification. The ctDNA concentration per nucleotide was determined by UV absorbance at 260 nm ( = 6600 L mol⁻¹ cm⁻¹). And Hela cancer cell lines, DMEM (Hyclone), Fetal bovine serum (sijiqing), penicillin-streptomycin (Sigma), 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) (Sigma), DMSO (Sigma), and phosphate buffer saline (Sigma) were used for determination of POM cytotoxicity. The elemental analysis of PMo₁₀V₂ was estimated by a Leaman inductively coupled plasma (ICP) spectrometer. Infrared spectrum was recorded in the range 400–4000 cm⁻¹ on a Nicolet Magna 560 FT/IR Spectrophotometer using KBr pellets. UV-Vis spectra of PMo₁₀V₂in different concentrations of ctDNA were recorded on a Shimadzu U-3010 Spectrophotometer with a 1 cm path length cell. The fluorescence spectra were recorded on a shimadzu RF-5301PC spectrofluorophotometer. The optical absorbance was read on a plate reader (BIO-RAD Co., USA) at a wavelength of 570 nm for MTT.

2.2. Synthesis of K₅PMo₁₀V₂O₄₀

The vanadium-substituted heteropolymolybdate K₅PMo₁₀V₂O₄₀(PMo₁₀V₂) was synthesized according to the literature [26] and identified by IR spectrum and elemental analysis.

2.3. Cytotoxicity and the Antitumor Activity In Vitro Assay

The antitumor activity of the PMo₁₀V₂ on the human cancer cells were tested by the MTT method as described in literature [27]. MTT is a dye that can accept a hydrogen atom. The surviving tumor cells can reduce the yellow MTT to a blue formazan, but the dead tumor cells do not possess this capability. Thus the number of survival cells could be calculated by the change of optical density. Hela cells line was used for in vitro MTT assay. DMEM medium supplemented with 10% fetal bovine serum and 50 μg/mL penicillin-streptomycin. K₅PMo₁₀V₂O₄₀and 5-fluorouracil (5-Fu) were sterilized by filtration prior to use. Each agent was dissolved in DMEM to generate the appropriate doses for experimentation. Nontreated cells (DMEM alone) were used as negative controls. The Hela cells were plated on the 96-well cell culture plates at a density of cells well⁻¹ for 24 h at 37°C in a 5% CO₂ incubator. After that the dilutions of PMo₁₀V₂ and 5-Fu at different concentrations were added and allowed to incubate for 24 h. After that the MTT solution (0.02 mL, 5 mg/mL in 0.01 M PBS) was added to each well. The cells were incubated for another 4 h at 37°C and then added DMSO 100 μL per well and shaked for 10 min at room temperature. The samples containing PMo₁₀V₂ was dissolved in DMEM medium at 800, 400, 200, 100, 50, 25, and 12.5 μg/mL concentrations. The 5-Fu was used as the positive control group with the concentration of 400 and 200 μg/mL in DMEM. The inhibition concentration was determined for each experimental group by comparison with MTT results from nontreated (DMEM alone) cells and calculated using the following formula:

2.4. ctDNA Binding Experiments

2.4.1. UV-Vis Absorption Spectra

The absorption titration experiments were performed in absence and presence of ctDNA by sequential addition of specified volume of ctDNA stock solution into a 1 cm path length cuvette containing PMo₁₀V₂ solution (100 μM/L) on a U-3010 UV-Vis spectrophotometer. After each addition of ctDNA solution, the absorption spectra were recorded from 200 to 700 nm. The intrinsic binding constant of PMo₁₀V₂ with ctDNA was calculated by using the following equation: where, , , and correspond to /[PMo₁₀V₂] and the extinction coefficient of free and fully bound PMo₁₀V₂, respectively [19]. A plot of /() versus [ctDNA]_T, where is the total concentration of ctDNA in the base pairs unit, gives as the ratio of the slope to intercept [18, 28].

2.4.2. Fluorescence Spectra

The interaction pattern of the PMo₁₀V₂ with ctDNA was determined by fluorescence titration method. Fluorescence measurements were carried out by keeping the concentration of PMo₁₀V₂ constant and varied concentrations of ctDNA. The fluorescence quenching experiment was performed with EB and the experimental data were plotted according to the Stern-Volmer equation (3): ( and are the fluorescence intensities in the absence and presence of the PMo₁₀V₂, respectively, is the concentration of PMo₁₀V₂ to ctDNA, and is the Stern-Volmer quenching constant which is dependent on the ratio of the bound concentration of EB to the concentration of ctDNA.) Excitation and emission slit widths were set as 5 and 10 nm, respectively. In competition binding experiments, the concentrations of EB and ctDNA were 100 μM and 450 μM, respectively, while PMo₁₀V₂ concentration varied from 0 to 80 μM. The 522 nm was chosen as the excitation wavelength and the emission spectra were recorded from 200 to 700 nm. The binding mode of PMo₁₀V₂ with ctDNA was obtained on the basis of previous published methods [19].

2.5. Statistical Analysis

Data were expressed as mean ± SD. All experiments were performed in triplicate, unless otherwise indicated. Statistical significance was evaluated by one way analysis of variance (ANOVA) combined with Duncan’s multiple range tests. The IC₅₀ values represent means of quadruplicate determination ±SD. MTT analysis of multiple comparisons were statistically analyzed using SPSS17 software (significance was established at ).

3. Results and Discussion

3.1. Determination of K₅PMo₁₀V₂O₄₀

The elementary analysis result of K₅PMo₁₀V₂O₄₀ is P, 1.47; Mo, 50.62; V 5.10(%) conforms to the calculated result: P, 1.59; Mo, 50.30; 5.23 V(%). The results of the IR spectra analysis to the compound PMo₁₀V₂ within the range from 400 cm⁻¹ to 4000 cm⁻¹ using KBr pellets are shown in Figure 1. As shown in Figure 1, the IR spectrum of PMo₁₀V₂ showed the characteristic asymmetric stretching vibrational peaks at 776, 588, 505 (Mo––Mo), 869 (Mo––Mo), 960 (Mo–), 1066 and 1214 cm⁻¹ (splitting of the triply degenerate PO4). These peaks suggest that the PMo₁₀V₂ are successfully synthesized.

3.2. Cytotoxicity and the Antitumor Activity In Vitro Assays

In order to evaluate the antitumor activity of PMo₁₀V₂, the MTT method was used to detect the activity for Hela cancer cell lines in vitro. A wide range of concentrations (12.5–800 μg/mL) of PMo₁₀V₂ and 5-Fu (200, 400 μg/mL) were tested for its toxicity on the Hela cancer cell line where a dose-dependent cytotoxicity of PMo₁₀V₂ was observed. The DMEM without drugs was used as control group. It shows that higher concentration of PMo₁₀V₂possesses high toxicity on the Hela cancer cells; at a lower concentration as 12.5 μg/mL there was no obvious sign of cell death. There is a significant difference between control group and experimental group. The inhibitory effect of PMo₁₀V₂ and 5-Fu is given in Table 1 and the IC₅₀ value of PMo₁₀V₂ is 800 μg/mL, which is more effective than the positive control, 5-Fu (). It can be concluded that the PMo₁₀V₂possesses the antitumor activity with a dose-dependent decrease in the Hale cells viability, as shown in Table 1 and Figure 2.

3.3. DNA Binding

3.3.1. Absorption Titration

The interaction of PMo₁₀V₂ with DNA was analyzed by UV-Vis absorption and fluorescence spectroscopic titration. Absorption titrations experiments were carried out to determine the binding mode of PMo₁₀V₂ with ctDNA by monitoring the absorption spectra of PMo₁₀V₂ in the absence and presence of ctDNA [29]. Figure 3 shows the absorption spectra of PMo₁₀V₂in the presence of different concentrations of ctDNA. In the UV region, the PMo₁₀V₂ performed an intense absorption band around 254 nm. Upon the addition of increasing concentration of ctDNA to PMo₁₀V₂ solution, a continuing increase in the absorption peak of PMo₁₀V without any red or blue shift was observed, shown in the Figure 3. The spectroscopic change suggests that there are interactions between PMo₁₀V₂ and ctDNA.

The titration absorption data were analyzed to evaluate the intrinsic binding constant , which can be calculated based on (2), which was given by the ratio of slope to the intercept in plots from the equation. As shown in the inset of Figure 2, the value of highly depends on the value of , where = [PMo₁₀V₂]/[ctDNA]. The value ( ) is much smaller than those reported characteristics of classical intercalators ( ) [30]. The phenomenon is indicating a weaker binding of ctDNA with PMo₁₀V₂ than with the classical intercalation interaction. According to the above results, the groove or outside stacking coordinate covalent binding is more probable than intercalative binding between PMo₁₀V₂ and ctDNA.

3.3.2. Fluorescence Spectroscopic Experiments

To further explore the PMo₁₀V₂interaction with ctDNA, a competition experiment with EB, known as the typical intercalator with ctDNA, was investigated. Fluorescent probe technology is a high sensitivity, selectivity detection methods. EB and NR are common used fluorescent probes. EB is a typical indicator of intercalation since it can form soluble complexes with nucleic acids emitting intense fluorescence in the presence of ctDNA due to its strong intercalation between the adjacent ctDNA base pairs. The fluorescence will decrease when the EB dissociate from ctDNA. It was previously reported that the enhanced fluorescence can be quenched by the addition of a second molecule which could replace the bound EB or break the secondary structure of the ctDNA [12, 31]. The Electron transfer or replacement of the molecular fluorophores mechanism has been proposed to account for the quenching effect. For further exploration of ctDNA-PMo₁₀V₂ interaction, the fluorescence emission of bound EB to ctDNA has been investigated in the presence of PMo₁₀V₂. The results in Figure 4 show the quenching effect of PMo₁₀V₂. Upon the addition of increasing concentration of PMo₁₀V₂, the fluorescence intensity can be quenched. And the reduction of fluorescence intensity depended on the addition of the PMo₁₀V₂. In the inset of Figure 4, the plots of versus [PMo₁₀V₂] was a straight line. According to the Stern-Volmer equation, the value of quenching constants was 4.89 × 10³ M⁻¹ which is much lower than the corresponding value of EB. PMo₁₀V₂ does not show any fluorescence whether in ctDNA absence or presence. The maximum binding constant of PMo₁₀V₂ to ctDNA is much lower than EB, according to the UV-Vis analyses. Hence PMo₁₀V₂is not expected to replace the strong bound EB. Therefore, the binding mode of PMo₁₀V₂ with ctDNA is not intercalation interaction. The result is consistent with the findings obtained from UV-Vis spectral studies.

4. Conclusion

In this study, the synthesis, characterization, antitumor activities, and ctDNA interaction of PMo₁₀V₂were investigated. The results of combined spectroscopic methods reveal that PMo₁₀V₂ bounds to ctDNA by groove or outside stacking binding mode and proved the presence of any direct coordinate covalent bond formation. This binding mode may be explained by considering the high capacity of this PMo₁₀V₂ for accepting electrons. These results show that PMo₁₀V₂ as antitumor agents possess high efficacy on Hela cells. The researches of pharmacodynamics, toxicology, and the interaction with DNA on PMo₁₀V₂ are being further tested.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors’ Contribution

Wen Qi and Ying Qin contributed equally to this study.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (81402719). China Postdoctoral Science Foundation (20100481064 and 2012T50307), Young Scholars Program of Norman Bathune Health Science Center of Jilin University (2013202015), and Jilin Agricultural Product Quality and Safety Project (2011-Y11).

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Copyright © 2015 Wen Qi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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