Research ArticleExperimental Studies

The Complex Composition of Trans-resveratrol, Quercetin, Vitamin E and Selenium Inhibits the Growth of Colorectal Carcinoma

JUSTYNA CZAPLA, ALINA DRZYZGA, SYBILLA MATUSZCZAK, EWELINA PILNY, TOMASZ CICHOŃ, KRZYSZTOF STOJECKI and RYSZARD SMOLARCZYK
Anticancer Research October 2022, 42 (10) 4763-4772; DOI: https://doi.org/10.21873/anticanres.15981

Abstract

Background/Aim: Numerous studies have demonstrated an anti-cancer action of plant-derived polyphenols. Their action is mainly related to antioxidant, anti-inflammatory, immunomodulatory and inhibitory properties. It is expected that proper composition of nutrition factors with anti-cancer activity may prevent from cancer incidence or inhibit cancer progression. The aim of the study was to investigate the anti-cancer properties of a standardized composition of compounds: trans-resveratrol, quercetin, vitamin E and selenium (Neoplasmoxan, Vebiot) in a mouse model of CT26 colorectal carcinoma. Materials and Methods: Colorectal carcinoma cells (CT26) were introduced subcutaneously (2×105/mouse) on the back of the mice. Neoplasmoxan suspension was administered intragastrically, daily, for 21 consecutive days. In collected tumors, the area occupied by tumor blood vessels and the number of immune cells; macrophages and CD8-positive cytotoxic T lymphocytes were evaluated. Results: It was observed that administration of Neoplasmoxan inhibits the growth of colorectal carcinoma in mice. Tumor volume after Neoplasmoxan administration was 40% smaller than in control groups. No overall toxicity of Neoplasmoxan was observed. The area of blood vessels in tumors of mice that received Neoplasmoxan was reduced by approximately 20%. The area occupied by macrophages increased about 60% compared to the control group. However, no increased number of CD8-positive cytotoxic T lymphocytes was observed in the group that received Neoplasmoxan. Conclusion: A tendency of Neoplasmoxan to inhibit the growth of colorectal carcinoma was recorded. It also seems that additional combination of the tested preparation with standard chemotherapy or radiotherapy should bring a synergistic therapeutic effect.

Key Words

Cancer and associated conditions are major public health issues. A similar situation is observed in veterinary medicine, with approximately 4.2 million dogs affected by cancer in United States yearly (1). Further, etiology, epidemiology and basic molecular mechanisms of cancer are common among dogs and humans, which makes dogs a suitable model for interspecies research. Also, similar diagnostics, treatment and prevention tools have been used in both veterinary and human medicine for treating neoplasm. Veterinarians use surgery, chemotherapy, radiotherapy, and nutrition approach (1-3).

Malnutrition is connected with 10-20% of death in cancer patients. This is the key argument for the importance of clinical nutrition in the course of neoplastic diseases. Also, other symptoms of disease might occur like loss of appetite, loss of body weight and sarcopenia, which lead to cachexia. Nutritional intervention ensures proper energy intake, macro/micronutrients management and hydration (4-6). Additionally, administration of plant-derived substances, mostly plant-derived polyphenols, might have impact on the genetic stability of cells, free radical scavenging, regulation of cell cycle, immunomodulation, downregulation of cancer angiogenesis and tumor cell migration (7).

All the aforementioned information suggests the importance of a balanced diet and proper supplementation of selected compounds in cancer patients. The same rationale applies to pet animals. It is achieved in several commercial solutions dedicated to pet animals, such as Vebiot Neoplasmoxan. This nourishment is proposed by the manufacturer for the following medical conditions: diagnosed cancer, aged animals and cancer predisposed breeds, palliative care patients to increase quality of life. The product contains plant-derived compounds: trans-resveratrol, quercetin, with the additive of selenium and vitamin E. Numerous in vitro and in vivo studies have been conducted in the context of using trans-resveratrol in cancer-related management. There are corresponding data for quercetin, pointing to the potential usage of these two polyphenols in the inhibition of the progression following type of cancers: mammary/breast cancer, pancreatic cancer, colon cancer, prostate cancer, hepatocellular carcinoma, lymphoma, human salivary adenoid cystic carcinoma, ovarian carcinoma, osteosarcoma, cervical carcinoma, lung cancer, glioma, glioblastoma, epidermoid carcinoma, melanoma, esophageal carcinoma, neuroblastoma, leukemia (8, 9). What is more, trans-resveratrol and quercetin have previously shown chemosensitization abilities (10, 11). For the ingredients of Neoplasmoxan, the following anticancer mechanisms of action have been proposed: induction of apoptosis, cell cycle regulation, reduction of metastasis, forkhead protein modulation, immunomodulation, reduction of cancer cell proliferation, reduction of angiogenesis, free radical scavenging (12, 13). The studies conducted so far on individual ingredients have been based on various types of research models, however, there were no studies done on such a composition of active ingredients as contained in Neoplasmoxan on in vivo tumor models. The aim of the study was to investigate the effectiveness of trans-resveratrol, quercetin, vitamin E and selenium composition in the treatment of an experimental mice colorectal carcinoma model.

Materials and Methods

Mice and ethics statement. Experiments were conducted on female mice BALB/c strain (8 to 10-week-old), obtained from Charles River Breeding Laboratories (Wilmington, MA, USA). Experiments on animals were carried out with the consent of the Local Ethics Commission of Animal Experiments in Katowice (permission No. 36/2022). Experiments were carried out according to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animals were treated in accordance with the 3R rule with all efforts to minimize animal suffering. Mice were housed in the Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch (Poland) in a pathogen-free facility in a HEPA-filtered (SPF standard) Allentown’s IVC System (Allentown Caging Equipment Co, NJ, USA). Mice received total pathogen-free standard and complete diet (Altromin 1314, Altromin Spezialfutter GmbH & Co. KG, Lage, Germany) and water ad libitum throughout the study.

Cell line, inoculation of animals. Murine CT26 (colon carcinoma cell line, ATCC, Manassas, WV, USA) cells were cultured in RPMI 1640 (Biowest, USA) supplemented with 10% heat-inactivated fetal bovine serum (EURx, Gdańsk, Poland) and antibiotics (penicillin and streptomycin, Merck, Darmstadt, Germany). Cell cultures were maintained in standard conditions: 37°C, 5% CO2, 95% humidity. Cells were passaged with 0.05% trypsin-EDTA every 3-4 days. Mice were injected subcutaneously (lower flank) with 2×105 CT26 cells in 100μl PBS. Tumors were measured with calipers every day and tumor volumes were determined using the following formula: volume=width2×length×0.52. Mice body weight was measured daily throughout the whole study. Mice with developed tumors (~10 mm3), on the 4th day after CT26 cells inoculation, were randomly divided into three treatment groups: Control, Compound A, Compound B. The study was blinded – the investigators were not aware which compound (A or B) contained treating substances until the end of the trial and analyses. After performing all the analyses, the trial was unblinded. Compound A contained bioactive agents: trans-resveratrol, quercetin, vitamin E and selenium (Vebiot Neoplasmoxan), Compound B microcrystalline cellulose (vehicle).

Therapeutic agents and therapy. Neoplasmoxan or microcrystalline cellulose (powder form) were introduced by oral gavage at a dose of 55 mg/kg of body weight in 200 μl of water for injection. Control group received by oral gavage 200 μl of water for injection. The factors were introduced every day, for 3 weeks since the 4th day post CT26 cell inoculation.

Tumor collection and histochemical staining. On the 25th day after CT26 cell inoculation mice were sacrificed by cervical dislocation and tumors were collected for immune and histochemical analyses. Tumors were embedded in cryo embedding matrix - Optimal Cutting Temperature compound (OCT) (Leica Biosystems, Wetzlar, Germany) and frozen in liquid nitrogen. Frozen tumors were sectioned into 5 μm slices and stained for histochemical examination (hematoxylin/eosin staining, Merck, Darmstadt, Germany). Imaging and the analysis of the specimens was conducted using the Nikon Eclipse 80i microscope (Nikon Instruments Inc., Tokyo, Japan).

Immunohistochemistry. The tumor vasculature was determined by staining endothelial cells in frozen sections using an antibody directed against CD31 antigen (ab7388, Abcam, Cambridge, UK), followed by Alexa Fluor 594 conjugated secondary antibody (ab150168, Abcam). The area occupied by blood vessels was counted with the ImageJ software (NIH, Bethesda, MD, USA). The presence of macrophages was determined by staining tumor sections using an antibody directed against F4/80 antigen (MCA497R, Bio-Rad Laboratories, Hercules, CA, USA), followed by Alexa Fluor 488 conjugated secondary antibody (ab150165, Abcam). The area occupied by macrophages was counted with the ImageJ software (NIH). The presence of T lymphocytes (CD8α-positive cells) was determined by staining frozen sections with antibody directed against CD8α antigen (ab22378, Abcam), followed by Alexa Fluor 594 conjugated secondary antibody (ab150168, Abcam). The number of CD8α-positive T lymphocytes was manually counted in at least 5 randomly chosen fields (magn. 20×) per section. To visualize cell nuclei, tumor sections were stained with DAPI (D8417, Merck, Darmstadt, Germany). For preserving fluorescence, the sections were mounted in VECTASHIELD Mounting Medium (H-1000, Vector Laboratories, Burlingame, CA, USA). Fluorescence imaging was performed with the confocal microscope LSM710 (Carl Zeiss Microscopy, Jena, Germany).

Statistics. Statistical analyses were performed using the Statistica 12 software (StatSoft). Data were expressed as mean±SEM. The normality of the distribution was verified with the Shapiro-Wilk test. For variables with normal distribution, the one-way ANOVA (with post-hoc Tukey HSD test) was carried out; otherwise, nonparametric test was performed (the Kruskal-Wallis followed by the post hoc multiple comparisons of rank sums test). p<0.05 was considered statistically significant.

Results

Inhibition of CT26 murine colorectal carcinoma growth. Four days after tumor cells implantation water, microcrystalline cellulose or Neoplasmoxan were daily administered orally for 21 consecutive days. Tumor growth inhibition was observed in a group that received Neoplasmoxan solution (Figure 1). The mean volume of tumors after Neoplasmoxan administration was 500 mm3 smaller (which was 40% of the tumor volume) than in the control group and the group that received microcrystalline cellulose. However, inhibition of growth was not statistically significant.

Figure 1.
Figure 1.

Growth inhibition of colorectal carcinoma. Mice with tumors were treated daily with the relevant compound. Tumors were measured with calipers (mean±SEM, upper chart). Individual tumor follow-up (bottom chart). Statistical analysis was performed with the Tukey’s HSD test.

Reduction of tumor weight after administration of Neoplasmoxan. Upon completion of therapy, on the 25th day after administration of tumor cells, mice were sacrificed, tumors were collected, photographed, and weighted. In the group of mice that received Neoplasmoxan, it was observed that tumors were smaller, and their weight was reduced compared to mice of control groups (Figure 2). Tumor weight was 39% less in the Neoplasmoxan group than in the control group and 30% less than in the Vehicle group.

Figure 2.
Figure 2.

Picture of individual tumors taken after tumor removal (upper graph). Tumor weight was measured, and statistical analysis was performed with the Tukey’s HSD test (bottom chart).

Lack of overall toxicity in mice after administration of Neoplasmoxan. Daily, oral administration of water, microcrystalline cellulose and Neoplasmoxan had no effect on the health of the mice and their well-being. The weight of the mice in the experiment did not change (Figure 3).

Figure 3.
Figure 3.

Weight of mice. Weight and general health condition were scored on a daily basis.

Absence of necrosis and immune cells infiltration in tumor tissues after Neoplasmoxan administration. The collected frozen tumors were cut into 5 μm thick sections and tissue sections were stained with a solution of Hematoxylin & Eosin Y. In obtained images of tumor tissues, no visible differences in the necrosis area and immune cell infiltration were observed between the groups (Figure 4).

Figure 4.
Figure 4.

Hematoxilin & Eosin (H&E) staining. H&E staining of CT26 murine colorectal carcinoma. Tumor sections were imaged using light microscopy. Lens magnification 10×.

Reduction of tumor blood vessels area after Neoplasmoxan administration. Tumor sections were stained with anti-CD31 antibody to determine tumor vasculature. Tumor blood vessel area was determined as the area of CD31-positive cells per mm2 of total tumor area (Figure 5A and B). Tumor blood vessel area was the smallest in the Neoplasmoxan group. The area of tumor blood vessels in the Neoplasmoxan group was about 20% smaller than in the control group and 45% smaller than in the Vehicle group (Figure 5B). The reduction in tumor vessel area of mice that received Neoplasmoxan was statistically significant at p<0.001.

Figure 5.
Figure 5.

Tumor blood vessel areas in tumors. (A) Tumor endothelial cells (CD31-positive cells, Alexa Fluor594, red) and nuclei (DAPI, blue) were visualized using confocal microscopy. The scale bar is 50 μm (magn. 20×). Representative images are shown. (B) Percentage of the blood vessels area was calculated (mean±SEM). Statistical analysis was performed with one-way ANOVA with the Tukey’s HSD post-hoc.

No change in the number of CD8-positive cytotoxic T lymphocytes after Neoplasmoxan administration. Tumor sections were stained with anti-CD8 antibody to determine the number of CD8-positive cytotoxic T lymphocytes (Figure 6A and B). CD8-positive cells were counted and presented as number of cytotoxic T lymphocytes per mm2 of tumor tissue. The number of CD8-positive T lymphocytes did not significantly change in any of the studied groups (Figure 6B).

Figure 6.
Figure 6.

Number of CD8-positive T lymphocytes in tumors. (A) CD8-positive cytotoxic T lymphocytes (Alexa Fluor594, red) and nuclei (DAPI, blue) were visualized using confocal microscopy. The scale bar is 50 μm (magn. 20×). Representative images are shown. (B) Total number of CD8-positive T lymphocytes was calculated per mm2 of tumor section (mean±SEM). Statistical analysis was performed with one-way ANOVA with Tukey’s HSD post-hoc.

Increased macrophages area in tumors after Neoplasmoxan administration. Tumor sections were stained with anti-F4/80 antibody to determine macrophage infiltration. Area of tumor macrophages was determined as the area of F4/80 positive cells per mm2 of total tumor area (Figure 7A and B). Macrophage area increased in the Neoplasmoxan and Vehicle groups. The macrophages area was about 60% higher in the Neoplasmoxan and Vehicle groups (Figure 7B). However, the changes were not statistically significant.

Figure 7.
Figure 7.

Macrophage areas in tumors. (A) Tumor sections were stained with the anti-F4/80 antibody. F4/80-positive macrophages (Alexa Fluor488, green) and nuclei (DAPI, blue) were visualized using confocal microscopy. The scale bar is 50 μm (magn. 20×). Representative images are shown. (B) Percentage of the area covered by macrophages was calculated per mm2 of tumor section (mean±SEM). Statistical analysis was performed with the Kruskal Wallis multiple comparisons test.

Discussion

There is no doubt that occurrence of cancer among companion animals is a significant concern of veterinary medicine (1). However, most of the research utilizing novel therapeutic approaches, including plant-derived compounds, has focused on laboratory animals in the context of translational research. The above is applicable also for two main compounds of Neoplasmoxan- trans-resveratrol and quercetin (8, 9). Direct testing of anti-tumor activity of plant extract on dogs was demonstrated, among others, for Capsicum chinense and Artemisia annua (with iron) (14, 15). However, preclinical research based on dogs is demanding, because of ethic and welfare concerns. There is definitely a need for prospective scientific research on new therapeutic solutions for dogs suffering from cancer.

Administration of plant-derived polyphenols: trans-resveratrol, quercetin, additive of selenium and vitamin E is effective in suppressing the growth of colorectal carcinoma in mice. The administration of Neoplasmoxan reduced the size of the tumors by approximately 40%, both in volume and in weight of the tumors (Figure 1 and Figure 2). Administration of Neoplasmoxan and microcrystalline cellulose did not result in systemic toxicity in mice. The weight of mice that received Neoplasmoxan did not change in relation to that of mice in control groups (Figure 3).

The effect of Neoplasmoxan was mainly based on inhibition of the formation of new tumor blood vessels. The area occupied by the vessels was significantly smaller after administration of Neoplasmoxan compared to control groups (Figure 5). Antiangiogenic features of resveratrol and quercetin have been widely described in the scientific literature. Including in vitro, xenograft and other in vivo experiments. Tseng et al. in their work concentrated on squamous cell and intracerebral glioma, found that resveratrol (i.p. administration) had significantly inhibited the tumor growth rate, enhanced survival time of the animals. Reduction of microvessel density in tumors was correlated with down-regulated expression of vascular endothelial growth factor (VEGF) (16). Similar findings have been proposed for the in vitro model of melanoma and the breast cancer xenografts in vivo model (17, 18). Subsequently, it has been found that resveratrol decreased VEGF-mediated phosphorylations of endothelial nitric oxide synthase, protein kinase B, and extracellular signal-regulated kinase (19). Inhibition of blood vessel growth has been also described for quercetin. In that context, molecular targets include the VEGFR-2-mediated angiogenesis pathway, downstream regulation of AKT factor, epithelial-to-mesenchymal transition (EMT), inhibition of STAT3 signalling pathway and c-Met activation. In vivo, angiogenic properties of quercetin were confirmed based on a BALB/c mice model of breast cancer (20). However, Igura et al. have shown that resveratrol is more potent angiogenesis inhibitor than quercetin in vitro (21).

Considering the immune system activation effect of the Neoplasmoxan there was no T lymphocyte-derived cytotoxicity observed. No increase in the number of CD8-positive cytotoxic T lymphocytes, which are significantly involved in the elimination of neoplastic cells, was observed. Apart from the well-known antioxidant action of resveratrol, the compound has an effect on the immune response, including modulation of macrophages, NK cells, dendritic cells, T cells and B cells. From the cancer metabolism perspective, this polyphenol is involved in SIRT1 pathway which is connected with anti-inflammatory action. Namely, resveratrol-induced stimulation of immune cells in the tumor microenvironment includes up-regulation of CD4+ T regulatory cells (Tregs) and CD4+ IL-10+ cells. On the other hand, resveratrol stimulates cytotoxicity of NK cells, which plays a key role in anticancer defense (22, 23). Quercetin, known for its antioxidant properties, has not been widely investigated as an immunomodulator. However, in work based on a zebrafish model Wang et al. showed significant immunostimulatory action of quercetin. In the quercetin-supplemented group acid phosphatase (ACP), myeloperoxidase (MPO) and complement components 3 and 4 (C3), C4, IgM were significantly upregulated. Expression of TNF-α, IL-8, TGF-β and IL-10 genes was also significantly increased in comparison to the control group (24). Similar findings were observed in a rat model, where gene expression of the same cytokines was up-regulated. In that experiment 50 mg of quercetin per kg of body weight, p.o., was administered to the animals (25). What is more, anticancer immune response, such as phagocytic activity of macrophages and NK cells activity were enhanced in BALB/c mice after quercetin supplementation in murine leukemia wehi-3 cells (26). Recently, it has been shown that quercetin attenuated the inhibitory effect of PD-L1 on T cells, preventing from PD-1/PD-L1 interactions with cancer cells, which collectively resulted in the reduction of tumor growth (27).

The individual ingredients of Neoplasmoxan have been found to exert a macrophage stimulatory effect. In this study, despite an increase in the number of macrophages in tumors following Neoplasmoxan or even vehicle administration, this change was not statistically significant. Increased macrophage infiltration plays a vital role in obtaining effective cancer therapy. Their polarization from the pro-cancer M2 phenotype to the anti-cancer M1 phenotype is particularly important (28). Increasing the percentage of macrophage cells in colorectal carcinoma tumors may also have a positive impact on the effectiveness of the applied therapy. The role of macrophages with pro-tumor (M2) or anti-tumor (M1) properties is well known. Macrophages, in particular M1 macrophages, apart from their cytotoxic activity, may also be responsible for the normalization of neoplastic blood vessels (29).

The combination of Neoplasmoxan with conventional cancer treatments, such as chemotherapy or radiotherapy could be beneficial. Reducing the number of blood vessels in the tumor, their normalization may have a beneficial effect on the effectiveness of chemotherapeutic agents. Improved vascularization facilitates drug distribution through increased tumor perfusion and better drug penetration into cancer cells (30, 31). Moreover, normalization of neoplastic blood vessels improves the effectiveness of radiotherapy by improving tumor oxygenation (32-34). Additionally, the normalization of tumor blood vessels reduces the possibility of neoplastic cells metastasis to other organs (30). The chemosensitization approach, seems to be promising perspective for phytocompounds. Previously, this phenomenon has been described for resveratrol-curcumin and quercetin-curcumin combinations (35, 36). Nessa et al., found that the highest level of drug-resveratrol synergism was shown when polyphenol was administrated 2h before chemotherapy (37). Due to drug dose reduction, there was also suggestion of chemotherapy side-effect limitation (38). Further research is required to provide applied evidence of the chemosensitization of various mixtures of plant-originated compounds.

In order to more effectively inhibit tumor growth, it seems that the combination of Neoplasmoxan with compounds that activate the immune system, especially cytotoxic lymphocytes, anti-cancer macrophages and NK cells, is necessary.

Conclusion

Administration of Neoplasmoxan inhibits the growth of colorectal carcinoma in mice. Tumor volume after Neoplasmoxan administration was 40% smaller than in control groups. No overall toxicity of Neoplasmoxan was observed. Neoplasmoxan administration reduced the area of blood vessels in tumors by approximately 20%. The area occupied by macrophages increased about 60% compared to the control group. However, no increased number of CD8-positive cytotoxic T lymphocytes was observed in the group that received Neoplasmoxan.

Acknowledgements

We sincerely appreciate other colleagues in our laboratory for their help and effort in this study. This study was supported by Nutrifarm Ltd.

Footnotes

  • Authors’ Contributions

    JC and AD conceived the original study design, performed immunofluorescence staining and analysis of T lymphocytes in tumors. SM performed analysis of blood vessels in tumor and all the statistical analyses. TC obtained ethical clearance from the Ethics Committee, conducted experiments on animals. EP performed immunofluorescence staining and analysis of macrophages in tumors. KS conceptualization of the study, contributed to interpretation of the data, article preparation. RS conducted experiments on animals, contributed to the data analysis, article preparation.

  • Conflicts of Interest

    The Authors received research support from Nutrifarm Ltd. The funders had no role in the collection, analyses, or interpretation of data. No potential conflicts of interest are disclosed.

  • Received July 26, 2022.
  • Revision received August 25, 2022.
  • Accepted August 26, 2022.

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The Complex Composition of Trans-resveratrol, Quercetin, Vitamin E and Selenium Inhibits the Growth of Colorectal Carcinoma
JUSTYNA CZAPLA, ALINA DRZYZGA, SYBILLA MATUSZCZAK, EWELINA PILNY, TOMASZ CICHOŃ, KRZYSZTOF STOJECKI, RYSZARD SMOLARCZYK
Anticancer Research Oct 2022, 42 (10) 4763-4772; DOI: 10.21873/anticanres.15981
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