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All issues Volume 29 / No 5 (October 2024) Wuhan Univ. J. Nat. Sci., 29 5 (2024) 461-470 Full HTML
Open Access
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Wuhan Univ. J. Nat. Sci.
Volume 29, Number 5, October 2024
Page(s) 461 - 470
DOI https://doi.org/10.1051/wujns/2024295461
Published online 20 November 2024

© Wuhan University 2024

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

0 Introduction

Cancer is a serious public health problem, which has threatened human health on a worldwide scale. At present, chemotherapy has been an important strategy and approach for cancer treatment. Therefore, identifying an effective and low-toxicity drug has become the priority in tumor treatment research[1-3]. In both clinical application and experimental exploration, most chemotherapeutic drugs mainly composed of synthetical compounds and adjuvant chemotherapeutic of natural substances or photochemicals. The synthetical compounds have attracted wide attention due to many advantages, such as designability, controllability and predictability. In recent years, it is worth noting that polyoxometalates (POMs) have become biomedical agents because of their versatile bioactivity including antibacterial, antitumor and antiviral functions[4-7]. Compared with current drugs, POMs hold unique advantages. Their composition, molecular structure and physiochemical properties are adjustable and can be easily synthesized from precursors[8-11]. Moreover, POMs have other advantages. Transition metals can be introduced into their structure to obtain transition metal-substituted POMs, such as mono, dis or tri-substituted polyanions[12-14]. The integration of transition metals with vacancy POMs modifies the original saturated POMs'composition, charge and physicochemical properties, thereby enhancing their biological activity[15,16].

In addition, owing to the low energy barrier between their oxidation states, low atomic radius (0.125 nm) in transition metal series, and high solubility in water, the ruthenium compounds are conducive to accumulation in cancer tissues. Thus, ruthenium compounds have potential value in the development of chemotherapeutic drugs[17,18]. The synergistic interaction between ruthenium and vacancy POMs is expected to endow ruthenium-substituted polyoxometalates (Ru-POMs) with high antitumor activity. Although a multitude of Ru-POMs have been reported[19-27], the antitumor activities of these compounds have rarely been explored or reported. In previous research, we investigated the antitumor activities of a monoruthenium(II)-substituted Dawson polyoxotungstate[28]. However, we noticed that most syntheses of Ru-POMs have predominantly relied on utilizing the monolacunary Keggin [XW11O39]n－ (X = P, Ge or Si) or Dawson-type [P2W17O61]10－ polyoxoanions as reagents or ligands for coordination with ruthenium[19-25]. And the compounds synthesized using other types of lacunary POMs combined with ruthenium were rarely reported.

Based on the aforementioned considerations, we chose trilacunary POMs β-[SiW9O34]10－ (β-SiW9) and RuCl3·nH2O as raw materials to synthesize a ruthenium multi-substituted polyoxometalate compound, designated as K7[SiW9O37Ru4(H2O)3Cl3]·15H2O (S1). The cytotoxicity of compound S1in vitro was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. And, the percentage of necrotic and apoptotic C33A (human cervical cancer) cells induced by the complex were also investigated by fluorescence microscopy and flow cytometry. Furthermore, the cell cycle distribution within C33A cells was detected by flow cytometry. Our results indicate that compound S1 can inhibit cell proliferation and induce apoptosis in cancer cells.

1 Experimental

1.1 Materials and Instrumentation

All reagents and solvents were commercially sourced unless otherwise specified. Ultrapure Milli-Q water was used in all experiments. β-Na9HSiW9O34·12H2O was prepared according to the reported methods[29]. RPMI 1640 was purchased from Sigma. C33A, DLD-1 (human colon cancer), HepG2 (human liver cancer), MRC-5 (human normal embryonic lung fibroblasts) cell lines were purchased from the American Type Culture Collection (Rockville, MD, USA). The elemental analysis for W, Ru, and K was performed using a Leeman inductively coupled plasma (ICP) spectrometer. Cl was analyzed by ion chromatography. Energy-dispersive X-ray spectroscopy (EDS) was performed by X-Max Extreme. Thermogravimetric analysis (TG) was carried out on a Pyris Diamond TG instrument under N2 with a heating rate of 10 ℃·min-1. Infrared spectra were recorded on a Perkin-Elmer Spectrum FT-IR (fourier-transform infrared spectroscopy) Spectrometer using KBr pellets. Raman spectrum was tested by the Raman spectrometer. Electronic absorption spectra (UV/Vis) were recorded on a Lambda 750 spectrophotometer. X-ray photoelectron spectroscopy (XPS) of Ru and W were collected on a VG ESCALAB MK II spectrometer equipped with a Mg Kα (1 253.6 eV) achromatic X-ray source. Solution electronic emission spectra in acetonitrile was recorded by Shimadzu 3100 spectrophotometer and Shimadzu RF-5301 PC spectrofluorometer. Cyclic voltammetry (CV) was obtained with CHI 630E instrument in a three-electrode system: a glassy carbon electrode (GCE, diameter 3 mm) served as the working electrode, a platinum wire acted as the counter electrode, and Ag/AgCl was the reference electrode.

1.2 Synthesis

The synthesis of S1 was performed as follows:

About 0.27 g of RuCl3·nH2O (corresponding to 1.1 mmol) was dissolved in 8 mL of water. Approximately one hour later, 1.0 g of solid β-Na9HSiW9O34·12H2O (equivalent to 0.37 mmol) was slowly added with vigorous stirring. The pH of the solution was subsequently adjusted to 5.5 using aqueous Na2CO3 (1 mol/L). Then the solution was heated to a temperature range of 70 - 80 ℃ and was stirred for half an hour. After cooling down, aqueous Na2CO3 was added to adjust the pH to 5.0. Subsequently, the solution was filtered to remove any solid impurities. The purified solution obtained was passed through an Amberlite cationic column (IR-120) in the K+ form for three times. Next, 1.0 g of KCl (equivalent to 13 mmol) was added to the solution under continuous stirring, resulting in the immediate precipitation of black solids. 24 h later, these black solids were collected by filtration. Calc.: W, 48.94; Ru, 11.94; K, 8.07; Cl, 3.15. Found: W, 49.75; Ru, 12.25; K, 8.19; Cl, 3.09. Molar ratio: W/Ru = 2.23.

1.3 Methods

1.3.1 Cytotoxicity assay in vitro

MTT assay was performed according to the standard procedures[30]. Cells were placed in 96-well microassay culture plates (8×103 cells per well) and cultured overnight in the incubator with 5% CO2. Subsequently, the test complex was added to the wells at final concentrations ranging from 2.5 to 100 µmol/L. Control wells were prepared by adding 200 µL of culture medium alone. The plates were then incubated for 24, 48 or 72 h at 37 ℃ with 5% CO2. Next, stock MTT dye solution (20 µL, 5 mg/mL) was added to each well. Following a 4-hour incubation, 150 mL of dimethylsulfoxide (DMSO) was added to solubilize the formazan crystals. The absorbance of each well was measured with a microplate spectrophotometer at a wavelength of 490 nm. The IC50 values were determined by plotting the percentage of cell viability against concentration and identifying the concentration corresponding to 50% cell viability relative to the control. Each experiment was repeated at least three times.

1.3.2 Apoptosis assay by Hoechst 33342 staining

C33A cells were seeded on chamber slides in six-well plates at a density of 2×105 cells per well and cultured in RPMI (Roswell Park Memorial Institute) 1640 medium supplemented with 10% fetal bovine serum (FBS). 24 h later, the medium was removed and replaced with fresh medium containing 0.05% DMSO by volume for 48 h. Subsequently, the medium was removed, and the cells were rinsed with ice-cold phosphate-buffered saline (PBS) before being fixed with 4% weight per volume formalin solution. Next, cell nucleuses were counterstained with Hoechst 33342 (10 mg/mL in PBS) for 10 min. Finally, the cells were visualized and imaged using a fluorescence microscope (Nikon, Yokohama, Japan) with excitation at 350 nm and emission at 460 nm.

1.3.3 Apoptosis assay

After chemical treatment, 2×105 cells were collected and rinsed with PBS. Then the cells were fixed with 70% ethanol, and stored at 4 ℃ for at least 12 h. Subsequently, the pellets were stained with a fluorescent probe mixture composed of 50 µg/mL propidium iodide and 1 mg/mL Annexin in PBS on ice under dark for 15 min. The instrument was set to measure fluorescence at wavelengths of 530 nm and 575 nm, with an excitation wavelength of 488 nm. To ensure statistical reliability, a minimum of 10 000 cells per sample were analyzed.

1.3.4 Cell cycle arrest analysis

C33A cells were seeded into six-well plates at a density of 2×105 cells per well and cultured in RPMI 1 640 supplemented with FBS (10%). 24 h later, the medium was removed and replaced with fresh medium containing 0.05% DMSO by volume for 24 h. Subsequently, Then the cell layer was trypsinized and washed with cold PBS and fixed with 70% ethanol. Subsequently, 20 µL of RNase (0.2 mg/mL) and 20 µL of propidium iodide (0.02 mg/mL) were added to the cell suspensions and incubated at 37 ℃ for 30 min. Finally, 10 000 cells were analyzed with a FACS (Fluorescence Activated Cell Sorter) Calibur flow cytometry system.

2 Results and Discussion

2.1 Synthesis and Characterization

Compound S1 was obtained by passing the solutions several times through an Amberlite cationic column in the potassium form, aiming to eliminate the possibility of excessive non-coordinated Ru. This indicates that Ru does not coprecipitate as a counter-cation with the potassium salts of the polyoxoanions but is instead included in the newly formed complexes with the trilacunary species. In other words, this suggests that four ruthenium atoms must be coordinated to one SiW9 anion. According to the elemental analysis, the ratio of W/Ru in the compound S1 is 2.23, which proves the presence of four Ru atoms per SiW9 unit. Additionally, ion chromatography analysis revealed three chloride ions per SiW9. The scanning electron microscope (SEM) of compound S1 is shown in Fig. 1(a). The existence of W, Ru, K, Cl, O was further confirmed by EDS (Fig. 1(b)). The TG curve of compound S1 (Fig. 2) displays a weight loss of 9.66% within the temperature range of 30 ― 325 ℃, corresponding to three coordinated water molecules and fifteen lattice water molecules (with a calculated value of 9.58%). Based on these analytical results and charge balance considerations, the molecular formula of compound S1 can be determined as K7[SiW9O37Ru4(H2O)3Cl3]·15H2O[31]. This compound likely has a structural similar to the previously observed Ni-substituted polyoxometalate, [PW9O34NiII3(OH)3(H2O)3Ni(H2O)3]4－ (PW9Ni4)[32], as shown in Fig. 3.

thumbnail Fig. 1 SEM image (a) and EDS (b) of compound S1

thumbnail Fig. 2 TG curve of compound S1

thumbnail Fig. 3 Possible structure of the Ru tetra-substituted anions [SiW9O37Ru4(H2O)3Cl3]7－ in compound S1

The IR spectrum of compound S1 is shown in Fig. 4. In the spectrum, characteristic bands at 1 002 cm-1, 955 cm-1, 895 cm-1, and 782 cm-1 are attributed to ν(Si―O), ν(W―Od) and ν(W―Ob/c―W), respectively[31]. The Raman spectrum of compound S1 showed fewer split bands: W―Od (953 cm-1), W―Ob―W (898 cm-1) and W―Oc―W (778 cm-1) (Fig. 5). The consistency of Raman and IR spectrum confirmed the stability of the compound S1 in aqueous solution.

thumbnail Fig. 4 IR spectrum of compound S1

thumbnail Fig. 5 Raman spectrum of compound S1

The UV/Vis of compound S1 in aqueous solution showed a high-intensity band in the visible region, centered approximately at 435 nm (Fig. 6), as has been observed in other RuIII polyoxoanions[33-36]. To identify the W/Ru oxidation states, XPS was employed. In the XPS spectra of compound S1, W 4f region displayed two partially overlapped peaks positioned at 35.18 and 37.38 eV, which are assigned to 4f7/2 and 4f5/2 of the W(VI) center (Fig. 7(a))[37]. Moreover, the binding energy peaks at 282.38 and 286.48 eV corresponds to 3d5/2 and 3d3/2 of the Ru(III) center, respectively (Fig. 7(b))[31].

thumbnail Fig. 6 UV/Vis absorption spectrum of aqueous solution of compound S1

thumbnail Fig. 7 XPS spectra of W 4f (a) and Ru 3d (b) in compound S1

2.2 Luminescence Spectra Studies

The solution-state fluorescent of S1 was investigated by fluorescence spectrum. Upon excitation at its excitation maxima, compound S1 exhibited an emission band at 685 nm. The emission profile and emission maxima were similar and independent of the excitation wavelength. The electronic emission spectral of compound S1 was presented in Fig. 8.

thumbnail Fig. 8 Fluorescence emission spectrum of the S1 in solution

2.3 Cyclic Voltammetry

To obtain the spectroscopic data, the redox behavior of compound S1 was investigated in a mixed electrolyte solution (pH = 3.0) containing Na2SO4 (0.5 mol/L) and H2SO4 (1 mol/L). Results showed that the cyclic voltammogram of RuCl3·nH2O did not exhibit any redox peak from -0.5 to 1.0 V. Subsequently, cyclic voltammetry (CV) measurements of compound S1 were conducted at a scan rate of 50 mV/s within the potential range from +1 000 to -700 mV in sulfate buffers with pH = 3 (Fig. 9). As shown in Fig. 9, the mean peak potentials (E1/2 = (Ecp + Eap)/2) for the I-I' reversible redox peaks are 300 mV, which was assignable to the RuIII/II couple[38].

thumbnail Fig. 9 Cyclic voltammograms of compound S1

2.4 Cytotoxicity Assay in vitro

The cytotoxicity of the S1, S2 (β-Na9HSiW9O34·12H2O) and S3 (RuCl3·nH2O) was determined in C33A, DLD-1, HepG2 and MRC-5 cell lines by MTT cell survival assay. These cells were treated with different concentrations of es S1, S2 and S3 for 24 h, 48 h and 72 h. As shown in Fig. 10(a), the es showed weak activities to the three cell lines for 24 h. The IC50 values of S1 were 74.06 µmol/L for C33A, 89.05 µmol/L for DLD-1 and more than 100 µmol/L for HepG2. The IC50 values of S2 and S3 to three cell lines were more than 100 µmol/L. Over a period of 48 h (as shown in Fig. 10(b)), compound S1 exhibited relatively weak activity against the C33A and DLD-1 cell lines, with IC50 values of 75.72 µmol/L and 89.73 µmol/L, respectively. Similarly, both S2 and S3 showed the weak activity to the three cell lines, with IC50 values close to 100 µmol/L. Upon extending the treatment to 72 h (Fig. 10(c)), the IC50 of the S1 was 45.48 μmol/L for C33A, 78.32 μmol/L for DLD-1 and 95.08 μmol/L for HepG2. Notably, none of complexes have cytotoxicity to the normal cell MRC-5 in different time points. The IC50 values of S1, S2 and S3 to these cells were displayed in Table 1. Cytotoxicity of some Keggin and lacunary-Keggin sandwiched polyoxotungstates towards Madin-Darby canine kidney (MDCK), Vero, HepG2, and MT-4 cells was investigated by using MTT. Results showed that none of the compounds exhibited toxicity at concentrations below 200 µmol/L in MDCK, Vero, and HepG2 cells[39]. These analyses exhibited that the complexes we studied possessed greater antitumor activity than previously reported. Obviously, the cell viability was both concentration-dependent and time-dependent, which indicated that compound S1 entered the cells slowly exerted a gradual killing effect. During the three cell lines, S1 showed the highest activity against C33A, followed by DLD-1 and HepG2. The differential cytotoxicity of these compounds toward the C33A, DLD-1 and HepG2 cell lines may be caused by their structural differences. The in vitro activity of anticancer drugs is often partially associated with their lipophilic character. And the resulting hydrophobicity could increase cellular uptake of the complex, thereby enhancing the antiproliferative activity. Alternatively, owing to the higher negative mitochondrial membrane potential present in cancer cells, lipophilic cations may preferentially cross the membrane and accumulate in mitochondria, leading to the observed higher uptake in cancer cells.

thumbnail Fig. 10 Cell viability inhibition induced by S1, S2 and S3

C33A, DLD-1 and HepG2 cells were treated with S1, S2 and S3 for 24 h (a), 48 h (b) and 72 h (c). Data from three independent experiments

Table 1

IC50values of compounds against human tumor cell lines and MRC-5 (unit:μmol/L)

2.5 Apoptosis Studies by Hoechst 33342 Staining and Flow Cytometry

Hoechst 33342, which stains the cell nucleus, is a membrane permeable dye with blue fluorescence. Under fluorescence microscopy, live cells exhibit uniformly light blue nuclei after Hoechst 33342 treatment, while apoptotic cells display bright blue nuclei due to karyopyknosis and chromatin condensation. Conversely, dead cells' nuclei remain unstained[40]. Subsequently, C33A cells were treated with S1 at 5 µmol/L, 25 µmol/L and 50 µmol/L for 48 h and followed by stained with Hoechst 33342. As shown in Fig. 11, under control conditions, cells displayed homogeneous nuclear staining. In contrast, treatment with S1 resulted in a dose-dependent increase in apoptotic C33A cells, characterized by bright staining, condensed chromatin, and fragmented nuclei. These results show that compound S1 effectively induces apoptosis in C33A cells.

thumbnail Fig.11 Hoechst 33342 staining of C33A cells induced by S1

To determine the percentages of apoptotic and necrotic cells, untreated C33A cells served as control, and apoptosis was investigated by flow cytometry (as shown in Fig. 12). In the control, the proportions of living cells and apoptotic cells were 99.6% and 0.3%, respectively. When C33A cells were exposed to compound S1 (5, 25, 50 µmol/L) for 48 h, the proportions of apoptotic cells were 3.6%, 11.6% and 54.5%, respectively. Compared with the control, the proportion of living cells decreased and apoptotic cells increased. These data demonstrate that the apoptotic effect of compound S1 on C33A cells exhibits a positive dose-responsive manner.

thumbnail Fig. 12 The percentage of living (C3), late apoptotic (C2), and early apoptotic (C4) in C33A cells

2.6 Cell Cycle Arrest

Flow cytometry analysis was utilized to assess the distribution of C33A cells in different phases of the cell cycle followed by propidium iodide staining. As shown in Fig. 13, treatment of C33A cells with 5 µmol/L, 25 µmol/L, and 50 µmol/L of compound S1 for 48 h resulted in a significant augmentation in the percentage of cells in the S phase, with increases of 2.5%, 7.9% and 16.5%, respectively. Moreover, compared to the control, treatment of C33A cells with 50 µmol/L of compound S1 for 48 h led to a decrease of 20.5% in the G0/G1 phase. These data demonstrate that S1 induce S phase arrest in C33A cells[41].

thumbnail Fig. 13 Cell cycle distribution of C33A cells induced by S1

3 Conclusion

In summary, the introduction of ruthenium into trilacunary POMs reaction system generated a ruthenium multi-substituted polyoxometalates. In vitro, compound S1 exhibits higher cytotoxicity toward C33A cell line compared to DLD-1 and HepG2 cell lines. Hoechst 33342 staining demonstrates that compound S1 effectively induces apoptosis in C33A cells. Apoptosis assay demonstrate a concentration-dependent increase in apoptotic cells upon treatment with compound S1. Furthermore, cell cycle arrest studies reveal that the antiproliferative effect of compound S1 on C33A cells occured in S phase. These findings suggest that ruthenium-substituted polyoxometalates can be used as new potential candidate for chemotherapy drugs in tumor therapy. However, the underlying mechanism of compound S1 on apoptotic induction in cancer cells needs further investigation.

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All Tables

Table 1

IC50values of compounds against human tumor cell lines and MRC-5 (unit:μmol/L)

In the text

All Figures

thumbnail Fig. 1 SEM image (a) and EDS (b) of compound S1
In the text
thumbnail Fig. 2 TG curve of compound S1
In the text
thumbnail Fig. 3 Possible structure of the Ru tetra-substituted anions [SiW9O37Ru4(H2O)3Cl3]7－ in compound S1
In the text
thumbnail Fig. 4 IR spectrum of compound S1
In the text
thumbnail Fig. 5 Raman spectrum of compound S1
In the text
thumbnail Fig. 6 UV/Vis absorption spectrum of aqueous solution of compound S1
In the text
thumbnail Fig. 7 XPS spectra of W 4f (a) and Ru 3d (b) in compound S1
In the text
thumbnail Fig. 8 Fluorescence emission spectrum of the S1 in solution
In the text
thumbnail Fig. 9 Cyclic voltammograms of compound S1
In the text
thumbnail Fig. 10 Cell viability inhibition induced by S1, S2 and S3

C33A, DLD-1 and HepG2 cells were treated with S1, S2 and S3 for 24 h (a), 48 h (b) and 72 h (c). Data from three independent experiments
In the text
thumbnail Fig.11 Hoechst 33342 staining of C33A cells induced by S1
In the text
thumbnail Fig. 12 The percentage of living (C3), late apoptotic (C2), and early apoptotic (C4) in C33A cells
In the text
thumbnail Fig. 13 Cell cycle distribution of C33A cells induced by S1
In the text

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