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DOI: 10.1039/D4DT02643H (Paper) Dalton Trans., 2025, 54, 631-640

Selenium-containing metallodrug overcomes cervical cancer radioresistance through physical–chemical dual sensitization†

Jianrong Cao‡ a, Fang Guo‡ a, Haiyan Jiang b, Chang Liu a, Junxian Guo a, Fei Cai a, Hao Lin a, Li Ma *a and Tianfeng Chen *a
aDepartment of Pharmacy of Puning People's Hospital, Department of Chemistry of Jinan University, State Key Laboratory of Bioactive Molecules and Druggalibility Assessment, MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangdong China510632, China. E-mail: chem_mali@jnu.edu.cn; tchentf@jnu.edu.cn
bGuangdong Province Research Center for Geoanalysis, Guangzhou 510080, China

Received 17th September 2024 , Accepted 20th October 2024

First published on 25th October 2024

Abstract

Radiotherapy is an important treatment for cervical cancer, but the efficacy of radiotherapy is often reduced in clinical practice owing to high frequency and high dose radiation leading to radiotherapy resistance. The development of efficient and low-toxicity radiotherapy sensitizers to reduce radiation dose is an effective strategy. Therefore, based on the existing radiotherapy sensitizers responding to radiophysical sensitization radiotherapy, we propose to design radiotherapy sensitizers with enzyme-mimicking and dual physical–chemical sensitization properties. In this work, we constructed Ru–Se complexes with cytochrome P450 enzyme-mimicking properties. On the one hand, the high concentration of ROS in tumor cells, along with the complexes, catalyzed the oxidation of intracellular active substances, breaking the redox balance of the cells and chemically sensitizing radiotherapy; on the other hand, the high atomic numbers of ruthenium and selenium responded to X-rays and physically sensitized radiotherapy. Experimental results demonstrated that the Ru–Se complexes can efficiently mimic cytochrome P450 enzyme activity and simultaneously respond to radiation dual sensitization radiotherapy, causing the expression of intracellular DNA damage response proteins. Thus, inhibition of repair protein expression overcomes radiotherapy resistance. This work provides a new idea for the development of efficient radiation sensitizers in the future.

1. Introduction

Cervical cancer is a major disease that threatens women's health worldwide.1–3 Clinically, radiotherapy is the main treatment for cervical cancer at different stages,4–6 but the cure rate of radiotherapy for cervical cancer is often low because of radioresistance caused by high-frequency, high-dose radiation.6–8 The development of highly effective and low-toxicity radiotherapy sensitizers is an effective strategy to reduce the dose and guarantee the efficacy of radiotherapy.9–11

Currently, there is a scarcity of clinically available radiotherapy sensitizers, and those that have been reported mainly utilize high atomic number atoms to physically respond to radiation and sensitize radiotherapy through the Compton effect and photoelectric effect.12,13 Therefore, we are interested in developing efficient radiotherapy sensitizers with multi-pathway sensitization to tumour properties.14–16 Based on the high and fragile redox homeostasis in cancer cells,17–19 we designed selenium-containing metal complex catalysts to mimic the activity of the cytochrome P450 enzyme,20 a multifunctional oxidoreductase,21,22 and disrupt intracellular redox homeostasis in cancer cells for chemosensitized radiotherapy.23–25 At the same time, we utilized the high atomic number elements ruthenium and selenium in the catalyst to affect radiation and physically sensitize radiotherapy (Fig. 1).26,27


image file: d4dt02643h-f1.tif
Fig. 1 Schematic of Ru–Se physico-chemical radiotherapy sensitization.

The 5-coordinated ruthenium complexes were formed by a valence-variable and ligand-stable ruthenium metal center in conjunction with the polydentate ligands 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (POP) and 1,10-phenanthroline.28 The ruthenium metal center contained an active ligand, Cl, serving as the catalytic site. We synthesized the three complexes Ru–C, Ru–N, and Ru–Se by replacing C atoms in 1H-imidazo[4,5-f] [1,10] phenanthroline with N and Se. The validation of the mimetic activity of the complexes demonstrated that the complexes mainly rely on the metal center to exert mimetic activity and that the substitution of Se, C, and N does not affect the mimetic activity. However, the introduction of high atomic number atoms, such as selenium, significantly enhances the sensitization effect during physically responsive X-ray-sensitized radiotherapy. This work provides a new direction for the development of safe and efficient radiosensitizers for radiotherapy via molecular design to achieve both chemical and physical sensitization to overcome cervical cancer radiotherapy tolerance.

2. Results and discussion

2.1 Synthesis and characterization of ruthenium complexes

Metallodrugs,29–32 particularly those containing ruthenium as the central metal ion,33–35 exhibit significant promise in tumor eradication by leveraging the diverse oxidation states of the metal ions to perturb cellular redox homeostasis within physiological settings.36–40 The tridentate ligand POP,41 which is a biocompatible ligand, and the bidentate ligand 1,10-phenanthroline have been employed to construct ruthenium complexes. The six-coordinated structure of the metal-centered ruthenium has five coordination sites in the full coordination state, which ensures the stability of the complexes. One dissociable site is left for the adjustment of the valence state of the metal center. Therefore, in this work, we synthesized Ru–C using Ru (POP) and imidazo[4,5-f]1,10-phenanthroline, Ru–N by replacing the carbon atoms between the two nitrogen atoms on the 1H-imidazo[4,5-f][1,10]phenanthroline with nitrogen atoms of similar atomic number, and Ru–Se by replacing the carbon atoms between the two nitrogen atoms on the 1H-imidazo[4,5-f][1,10]phenanthroline with selenium atoms of similar electronegativity (Fig. 2a). The effect of Ru–Se for radiotherapy sensitization was explored by comparison of the three types of complexes. The successful synthesis of the complexes was demonstrated by ESI-MS (Fig. S2–S4†), 1H NMR (Fig. S5–S7†), HPLC (Fig. S8–S10†) and elemental analysis. One of the indicators employed to evaluate the efficacy of a substance as a catalyst for redox reactions is the half-wave potential of the substance in question. Consequently, the cyclic voltammetric curves of Ru–C, Ru–N, and Ru–Se were determined by electrochemical scanning. The experimental results demonstrate that all three complexes exhibit two reversible oxygen reduction peaks (Fig. 2b), indicating that the substances have undergone two valence state transitions. Additionally, the three complexes display comparable half-wave potentials (Table S1†), suggesting that the activation energies required for redox reactions are similar and that their capacity to act as catalysts may also be comparable. Meanwhile, as can be observed from the density functional theory (DFT) calculations (Fig. 2c), the energy differences between the LUMO and HOMO orbitals of Ru–C, Ru–N, and Ru–Se are comparable, indicating that the synthesized complexes exhibit similar redox properties. This suggests that the introduction of distal atoms does not significantly affect the metal centres.
image file: d4dt02643h-f2.tif
Fig. 2 (a) Structural formulas for Ru–C, Ru–N and Ru–Se.(b) Cyclic voltammograms of Ru–C, Ru–N, Ru–Se in 0.1 M (nBu)4NPF6 CH3OH solution. Scan rate = 25 mV s−1. SCE refers to saturated calomel electrode. (c) HOMO–LUMO structures with the energy level diagrams of Ru–C, Ru–N, Ru–Se.

2.2 Ruthenium complexes with good enzyme-mimetic properties

Cytochrome P450 enzymes are among the most versatile biocatalysts in nature, catalyzing different types of redox reactions in vivo, mainly dehydrogenation and oxidation reactions.21,42 Therefore, the enzyme-mimetic properties of ruthenium complexes were validated by means of dehydrogenation of alcohols and oxidation of olefins. From the experimental results of the catalytic hydrogenation of alcohol substrates (Table 1), it can be seen that the yield of p-benzyl alcohol was 37.0% when there was no catalyst present, and, when the ruthenium complex was added, the catalytic yield was more than 95.0%. It was found that the catalytic efficiency of the other alcohol substrates could reach 100.0% (Table S2†), which indicated that our synthesized complexes had a better catalytic effect for catalytic dehydrogenation reaction. Next, we carried out oxidation catalysis on olefinic substrates (Table 2). When there was no catalyst present, the catalytic yield for styrene was 0.8%, and, after the addition of ruthenium complexes, the catalytic yield was more than 87.0%. The expansion of other olefinic substrates found that the catalytic yields were significantly improved (Table S3†), indicating that ruthenium complexes have the effect of catalyzing oxidation reactions. The results of the enzyme mimetic characterization are consistent with the previous electrochemical scans and DFT calculations, and Ru–C, Ru–N, and Ru–Se all have good redox catalytic efficiency; this result motivates us to continue to explore their effects in the cell.
Table 1 Performance of alcohol catalyzed by different ruthenium complexesa

image file: d4dt02643h-u1.tif
Catalyst Yieldb (%)
a Reaction conditions: 2.5 mM catalyst and 1000 mM substrate. b Yield was calculated based on oxidant.
— 37.0
Ru–C 99.0
Ru–N 97.0
Ru–Se 100.0

Table 2 Performance of olefins catalyzed by different ruthenium complexesa

image file: d4dt02643h-u2.tif
Catalyst Yieldb (%)
a Reaction conditions: 2.5 mM catalyst and 1000 mM substrate. b Yield was calculated based on oxidant.
— 0.8
Ru–C 87.6
Ru–N 89.2
Ru–Se 92.0

2.3 Ru–Se has a dual physical–chemical sensitizing effect

The prerequisite for a material to be useful is to have good stability, so we used UV-visible spectroscopy to test the stability (Fig. S8†) of the complexes in PBS, DMSO, and DMEM for 48 h. We found that the UV-absorption spectra of the complexes did not change with the increase of time, which indicates that our synthesized complexes have good stability as biomaterials.

Consequently, we examined the cytotoxicities of Ru–C, Ru–N, Ru–Se, and cisplatin on HeLa cells and radiotherapy-tolerant HeLa (R-HeLa) cells by MTT assay. We were excited to find that, although Ru–C, Ru–N, and Ru–Se exhibited similar oxidoreductase activities in extracellular catalytic assays, Ru–Se showed better antitumor activity at 0 Gy (Fig. 3a). It was postulated that the presence of Se atoms resulted in a slight reduction in the half-wave potential of the complexes, thereby enhancing the ability of Ru–Se to disrupt the redox equilibrium of the tumor, leading to the enhanced anti-tumor activity of Ru–Se. This experimental outcome also validated the efficacy of our chemosensitisation design. Next, we combined the X-ray to investigate the physical sensitization effects of Ru–C, Ru–N, Ru–Se, and cisplatin on HeLa cells (Fig. 3b and d), and the cytotoxicity showed that Ru–Se still showed the best anti-tumor activity. Based on the isobologram analysis, the IC50 of Ru–C (Fig. S9†), Ru–N (Fig. S10†), and Ru–Se combined with X-ray (4 Gy) were within the line connecting the IC50 of X-ray alone and Ru–C, Ru–N, and Ru–Se alone, demonstrating that the ruthenium complexes designed in this work have a sensitizing effect on radiotherapy. The experimental results show that both ruthenium and selenium, with high atomic numbers, exhibit physical sensitization, resulting in the superior radiotherapy sensitization effect of Ru–Se. For R-HeLa cells, the same trend was observed (Fig. 3c and e). The above experimental results suggest that Ru–Se can improve the sensitivity of radiotherapy through dual physical–chemical sensitization.


image file: d4dt02643h-f3.tif
Fig. 3 (a) The IC50 of Ru–C, Ru–N, Ru–Se and cisplatin without X-ray on HeLa and R-HeLa cells. (b) The IC50 of Ru–C, Ru–N, Ru–Se and cisplatin with X-ray on HeLa cells. (c) The IC50 of Ru–C, Ru–N, Ru–Se and cisplatin with X-ray on R-HeLa cells. (d) Isobologram analysis of the synergistic antiproliferative effect of the combined treatment of X-ray and Ru–Se on HeLa cells. (e) Isobologram analysis of the synergistic antiproliferative effect of the combined treatment of X-ray and Ru–Se on R-HeLa cells. (f) Clonogenic assay treated by different complexes (2 μM) with or without X-ray for 8 days in HeLa cells. (g) Colony formation results of HeLa cells treated with different complexes (2 μM) without X-ray. (h) Colony formation results of HeLa cells treated with different complexes (2 μM) with X-ray.

We used a colony formation assay to further assess the sensitizing effect of Ru–Se to X-ray43 (Fig. 3f). The survival rate was 54.1% when HeLa cells were treated with X-ray alone, and the survival rate with Ru–Se alone was 4.4%, which showed that Ru–Se alone could effectively inhibit cell proliferation, and its effect was much better than those of Ru–C and Ru–N. After combining the complexes with X-ray, Ru–Se was found to have the lowest survival rate, in agreement with the above experimental results.

2.4 Ru–Se combined radiotherapy induces cellular Sub-G1 cycle arrest and mitochondrial damage

In order to more visually assess the killing effect of Ru–Se combined radiotherapy on HeLa cells, the live cells were stained with Calcein-AM probe. The experimental results demonstrated that the Ru–Se exhibited the lowest number of surviving cells following treatment with the same concentration of different complexes (Fig. 4a). Furthermore, the number of living cells in the Ru–Se was significantly reduced following combined radiotherapy. This experimental result was also in accordance with the findings of the MTT toxicity assay. Having established the efficacy of Ru–Se in killing tumour cells, we were driven to investigate the mechanism by which Ru–Se inhibits tumour proliferation.
image file: d4dt02643h-f4.tif
Fig. 4 (a) Fluorescent images of living HeLa cells with different complexes (2 μM) combined with or without X-ray for 48 h by staining with Calcein-AM. (b) The numbers of living HeLa cells after incubation with different complexes (2 μM) combined with or without X-ray for 48 h by staining with Calcein-AM. (c) Cell cycle distribution of HeLa cells measured using flow cytometry after incubation with different complexes (2 μM) combined with or without X-ray for 48 h. (d) The results of cell cycle distribution of HeLa cells after incubation with different complexes (2 μM) combined with or without X-ray for 48 h.

One of the mechanisms through which drugs inhibit tumour proliferation is by inducing cell cycle arrest.44 Propidium iodide (PI) is a fluorescent dye that is used to detect double-stranded DNA. When combined with double-stranded DNA, PI fluoresces, and the fluorescence intensity is proportional to the amount of double-stranded DNA present. Flow cytometry is a technique that allows for the determination of DNA content in cells, which in turn enables cell cycle analysis. Therefore, to explore the effects of different complexes on the cell cycle (Fig. 4b), we added the same concentration of different complexes for cell cycle assay, and the experimental results show that Ru–C and Ru–N before and after X-ray almost do not affect the cell cycle, while Ru–Se can lead to Sub-G1 cell cycle arrest. The cell cycle arrest at the Sub-G1 phase was elevated from 12.82% to 26.64% after Ru–Se combined with X-ray. Presumably, Ru–C and Ru–N at this concentration do not affect the cell cycle change, although Ru–Se can still lead to cell damage at this concentration, making the cells undergo cycle arrest.

In the event of an excess of intracellular ROS, the mitochondria of the cell may be damaged,45 which in turn leads to a decrease in the mitochondrial membrane potential. JC-1 is a fluorescent probe that is employed to identify alterations in mitochondrial membrane potential (Δψm). Δψm is a crucial indicator for the assessment of mitochondrial function. As can be seen from Fig. 5a, the Δψm of the control group was 0.50% for cells not administered with the complex, and the change in mitochondrial membrane potential following the X-ray alone showed no significant changes. Following the addition of the complex Ru–Se, the Δψm was 12.25%, indicating that the complex alone was able to induce damage to cellular mitochondria. In combination with X-ray, the Δψm was 39.47%. This indicates that Ru–Se has good antitumor activity and can also be used in conjunction with X-ray to enhance the antitumor effect. The mitochondrial membrane potential was detected with the same concentration of Ru–Se and cisplatin on R-HeLa cells, and the effects were compared (Fig. 5c). It was found that cisplatin had no discernible effect on the mitochondrial membrane potential, while Ru–Se exhibited a clear impact.


image file: d4dt02643h-f5.tif
Fig. 5 (a) Flow cytometric analysis of mitochondrial membrane potential on HeLa cells treated with different complexes (2 μM) combined with or without X-ray for 48 h. (b) JC-1 fluorescence images of HeLa cell mitochondria treated with different complexes (2 μM) combined with or without X-ray for 48 h. (c) Flow cytometric analysis of mitochondrial membrane potential in R-HeLa cells treated with different complexes (2 μM) combined with or without X-ray for 48 h. (d) The results of mitochondrial membrane potential on R-HeLa cells treated with different complexes (2 μM) combined with or without X-ray for 48 h.

2.5 Ru–Se combined radiotherapy activates DNA damage protein response leading to apoptosis

To further investigate the mechanism of action of ruthenium complexes at the protein level, we performed western blotting experiments46 (Fig. 6a). Phosphor-histone H2A.X (p-H2A.X) and phospho-BRCA1 (p-BRCA1) are typical DNA damage-related proteins.47–49 As shown in Fig. 6b, the combination of Ru–Se radiotherapy increased the expression of p-H2AX and p-BRCA1. Furthermore, it induced PARP cleavage, which is considered a marker of apoptosis.50 The p53 protein plays a key role in apoptosis by detecting DNA damage in cells and triggering apoptosis when abnormalities occur.51 Our experimental results (Fig. 6c) showed that the Ru–Se combination radiotherapy group up-regulated the expression of p-p53, which activated the apoptotic pathway and led to cell death. XRCC1 is essential for the repair of DNA damage caused by ionizing radiation,52,53 and the Ru–Se combination radiotherapy group overcame radioresistance by inhibiting its expression and increasing the sensitivity of HeLa cells to radiation.
image file: d4dt02643h-f6.tif
Fig. 6 (a) Schematic of the anticancer mechanism of co-treatment of Ru–Se and X-ray. (b) Western blotting analysis of different complexes (2 μM) in combination with or without X-ray on the expression of apoptosis-related proteins. (c) The protein expression of p-p53 on HeLa cells treated with Ru–Se. (d) The protein expression of XRCC1 on HeLa cells treated with Ru–Se.

3. Conclusion

In conclusion, we constructed Ru–Se complexes for dual-pathway radiotherapy sensitisation in this work. On one hand, chemical sensitisation was achieved by mimicking the activity of cytochrome P450 enzymes, which catalyse redox reactions. On the other hand, physical sensitisation was achieved by exploiting the Compton effect and photoelectric effect, which the high atomic number atoms Ru and Se have when they combine with X-ray. The study demonstrated that Ru–Se exhibited the most pronounced cytotoxicity and radiosensitization effect on HeLa and R-HeLa cells, outperforming Ru–C, Ru–N, and cisplatin. This experimental outcome validated the efficacy of our physical–chemical dual sensitization design. The subsequent mechanism study revealed that Ru–Se combined with X-ray induced cell cycle arrest, promoted the expression of intracellular DNA damage response proteins, and activated proteins related to the apoptosis pathway, ultimately leading to cell apoptosis. Concurrently, the inhibition of pro-survival proteins overcame the resistance to radiotherapy, thereby achieving the objective of overcoming the radiotherapy resistance of cervical cancer cells through dual physical and chemical sensitization effects. This work presents a novel approach to the development of sensitizing agents for radiotherapy, offering a promising avenue for future research.

4. Experimental

Ru–C, Ru–N, and Ru–Se were prepared according to procedures reported in the literature. Experimental details of the synthesis, characterization, and biological studies of Ru–C, Ru–N, and Ru–Se are provided in ESI.†

Author contributions

L. Ma and T. Chen designed the experiments and wrote the draft. J. Cao and F. Guo performed the experiments. H. Jiang, C. Liu, J. Guo, H. Lin and F. Cai performed the complexes synthesis. All authors analysed the data and reviewed the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

The authors declare no conflict of interest.

Note added after first publication

Since publication of the accepted manuscript, ref. 11, 31, 32 and 34 have been added and the reference list and in-text citations re-numbered accordingly.

Acknowledgements

This study was supported by the National Science Fund for Distinguished Young Scholars (82225025), the National Natural Science Foundation of China (22177038, 21877049, 32171296, 82372103), and the Guangdong Natural Science Foundation (2020B1515120043, 2022A1515012235), Jinan University for the cultivation of Top-Notch Innovative Talents for Doctoral Students (2022CXB008).

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4dt02643h
‡ These authors contributed equally to the work.
This journal is © The Royal Society of Chemistry 2025
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