Research ArticleExperimental Studies

Combination Therapy with Glucan and Coenzyme Q10 in Murine Experimental Autoimmune Disease and Cancer

VACLAV VETVICKA and JANA VETVICKOVA
Anticancer Research June 2018, 38 (6) 3291-3297; DOI: https://doi.org/10.21873/anticanres.12594

Abstract

Background/Aim: Coenzyme Q10 is a well-accepted anti-oxidant agent known to play a protective role in various physiological and disease processes. Recently, Coenzyme Q10 is gaining attention as a substance with significant anti-inflammatory properties. β-Glucan is the most studied immunomodulator with significant synergetic effects with numerous bioactive molecules. We aimed to evaluate the possible synergistic effects of simultaneous use of coenzyme Q10 with the well-established immune modulator, β-glucan, on immune reactions and cancer development. Materials and Methods: Coenzyme Q10 and β-glucan were used, both in vivo and in vitro, and their effects were evaluated using phagocytosis and cytokine secretion. Results: Our study confirmed the strong anti-inflammatory effects of coenzyme Q10 and showed that these effects were further potentiated with the addition of β-glucan. The anticancer effects of coenzyme Q10 were less pronounced, but stronger, with the addition of β-glucan. Conclusion: There is significant synergy between coenzyme Q10 and β-glucan.

Coenzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is an essential substance for electron transport in oxidative phosphorylation, and forms an important component in the respiratory chain at the mitochondrial level. It is a lipophilic molecule present in the inner side of mitochondrial membrane. Commercially, it usually exists in the form of ubiquinone, but for the real biological effects, its reduced form, ubiquinol, should be utilized.

In addition to functioning as an electron carrier, CoQ10 also serves as an important antioxidant. Numerous reports evaluating the biological effects of CoQ10 have found decreased LPS-induced release of TNFα (1). Other studies have revealed significant anti-inflammatory, antiangiogenic, and anti-nociceptive activities probably via suppressing the level of nitric oxide (2). In rodents, CoQ10 inhibited the oxidative damage in blood, heart, kidney, and liver (3). Additional studies have shown prevention of atherosclerosis by attenuation of LDL oxidation and endothelial lesions (4), improving quality of life in patients with end-stage heart failure (5) and antiaging effects (6). In addition to the effects on various aspects of immune system, CoQ10 was also found to positively affect fatigue (7), have positive effects on type 1 and type 2 diabetes mellitus (8), and serve as a preventive agent against microcystin-LR–induced toxicity acting via modulation of oxidative stress (9).

Further studies have shown suppression of TNFα and IL-2 secretion by human blood cells after CoQ10 supplementation, suggesting possible mechanisms affecting immune functions (10). In addition to anti-inflammatory effects, CoQ10 also induced Treg (11) in graft versus host disease (12); some studies have suggested a possible role in the inhibition of carcinogenesis (13, 14).

A detailed study of the mechanisms of action revealed that actions of CoQ10 are mediated via inhibition of NFĸB/AP-1 activation and induction of Nrf2/ARE signaling (15). Most of the studies are based on supplementation with CoQ10. One study, however, described a case of a girl with immune dysregulation and CoQ10 deficiency. All conditions significantly improved after immunoglobulin and CoQ10 replacement therapy (16).

β-Glucans are structurally complex homopolymers of glucose, isolated from various sources including yeast, fungi, and wheat. Their role as biologically active immunomodulators has been well documented for more than 50 years (17-20). The positive effects of β-glucan treatment have been repeatedly confirmed in clinical trials (21).

Despite being the most studied immunomodulator, β-glucan is clearly not the only known immunomodulator. Scientists are increasingly experimenting with improvements of β-glucan action by adding additional immunomodulators. Therefore, combinations of various natural immunomodulating molecules are becoming more popular. The most common feature of these mixtures is β-glucan, which, 20 years ago, was found to have strong synergy with vitamin C (22). Later studies have found strong synergy between yeast-derived β-glucan and humic acid, with potentiated phagocytosis, cytokine release, and protection against hepatotoxicity (23). Recently, our group found that β-glucan combined with resveratrol and vitamin C showed significant improvements in stimulation of both cellular and humoral immunity, including anticancer activities (24). Additional findings indicated that adding Withania somnifera extract to the Maitake mushroom β-glucan significantly regulates stress-induced increase on corticosterone levels (25). The aim of this study was to evaluate the possible synergistic effects of glucan and CoQ10 on immune reactions and cancer development.

Materials and Methods

Materials. RPMI 1640 medium, HEPES, penicillin, streptomycin, carrageenan, cyclophosphamide, TNFα, and methotrexate were purchased from Sigma (St. Louis, MO). Fetal calf serum (FCS) was purchased from Hyclone Laboratories (Logan, UT, USA). Incomplete Freund's adjuvant was purchased from Difco Laboratories, Detroit, MI, USA). CoQ10 with ubiquinol content over 30% was purchased from Kaneka (Pasadena, TX, USA).

Cell lines. RAW264.7, Ptas64, and Lewis lung cancer cell lines were obtained from the ATCC (Manassas, VA, USA) and maintained in RPMI 1640 medium containing HEPES buffer supplemented with 10% heat-inactivated FCS, 100 U/ml penicillin and 100 μg/ml streptomycin, in plastic disposable tissue culture flasks at 37°C in a 5% CO2/95% air incubator.

Animals. Female, 8-week-old BALB/c mice were purchased from the Jackson Laboratory (Bar Harbor, ME). All animal work was done according to the University of Louisville IACUC protocol. Animals were sacrificed by cervical dislocation. Adjuvant arthritis (AA) was induced by a single intradermal injection of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. Methotrexate treatment consisted of oral doses of 0.3 mg/kg twice a week. CoQ10 was used at 1 mg/mouse dose, glucan at 100 μg/mouse.

Carrageenan-induced inflammation. A carrageenan-induced inflammation in the air pouch technique was used as described previously (2).

Immunological tests. Supernatants from cultured cells were tested by ELISA assay according to manufacturer's instructions using a Quantikine mouse IL-1α and IL-1β kit (R&D Systems, Minneapolis, MN). The technique employing phagocytosis of synthetic polymeric microspheres was described by Vetvicka et al. (26). For evaluation of possible inhibition of TNFα-mediated inflammatory reaction, Griess assay was performed as described (27). For evaluation of imultaneous phagocytosis and oxidative burst, the double fluorescence of FITC-labeled Staphylococcus aureus cells and hydrohyethidine oxidized to ethidium bromide was tested by flow cytometry as described (28).

View this table:
Table I.

Effect of CoQ10 and glucan on carrageenan-induced inflammation in the air pouch model.

Breast cancer model. Mice were injected directly into the mammary fat pads with 1×106/mouse of Ptas64 cells in PBS. The experimental treatment was begun after palpable tumors were found (usually 14 days after injection of cells) and after mice were assigned to experimental groups. Experimental treatment was achieved by intraperitoneal injections of tested samples diluted in PBS (once/day for 14 days). After treatment, the mice were sacrificed, and tumors removed and weighed (29).

Lung cancer model. For Lewis lung carcinoma therapy, mice were injected IM with 1×105 of Lewis lung carcinoma cells. Cyclophosphamide (30 mg/kg) was used IP at day 8 after tumor application (positive control), individual substances were used from day 0 to day 14 after tumor application. The control group of mice (negative control) received IP PBS daily. Each group held a minimum of five mice. At the conclusion of the experiment (day 14), mice were euthanized, their lungs were removed and fixed in 10% formalin, and the number of hematogenic metastases in lung tissue was estimated using a binocular lens at 8x magnification.

Results

Glucan is a natural immunomodulator, originally supposed to influence natural immunity only. Not surprisingly, phagocytosis remains to be one of the most commonly studied reactions. For the glucan administration, we used a dose of 100 μg/mouse, which is the most commonly used dose for glucan experiments in mice. CoQ10 was used at 1 mg/mouse dose, based on our preliminary experiments using a 500 mg/mouse to 5,000 mg/mouse range (data not shown). Data summarized in Figure 1 show that a glucan–CoQ10 combination improves the effects of glucan.

In the air pouch model, CoQ10 significantly reduced the exudate volume, total number of leukocytes, and nitrite formation. Glucan alone had similar, but less pronounced effects. A glucan–CoQ10 combination had stronger effects, particularly on lowering the nitrite production and total number of leukocytes (Table I).

To examine the potential therapeutic function of CoQ10 and glucan in inflammatory reaction of macrophages, we used macrophage cell line, RAW264.7. We incubated these cells with 10 ng/ml TNFα, in the presence or absence of 20 μM CoQ10 and/or 10 μg glucan. As shown in Figure 2, both agents alone or in combination significantly abolished the levels of nitrite formation caused by TNFα. Similar results were found in case of IL-1β production (Figure 3). In both cases, the glucan–CoQ10 combination had stronger effects.

Figure 1.
Figure 1.

Effect of oral administration of individual samples on phagocytosis by peripheral blood monocytes. Each value represents the mean±SD. *Represents significant differences between control (PBS) and tested samples at p≤0.05 level. All experiments were performed in triplicate.

Figure 2.
Figure 2.

Effect of CoQ10 and/or glucan addition on TNF-α-mediated NO synthesis by RAW264.7 cell line. Each value represents the mean±SD. *Represents significant differences between control (PBS) and tested samples at p≤0.05 level. All experiments were performed in triplicate.

For further evaluation of the possible synergy between glucan and CoQ10, we measured the level of IL-1α in plasma. In animals with AA, CoQ10 had only limited effects, compared to methotrexate monotherapy. Surprisingly, glucan treatment showed the same effects as methotrexate alone. The glucan–methotrexate–CoQ10 combination was the most active treatment (Figure 4).

Figure 3.
Figure 3.

Effect of CoQ10 and/or glucan addition on TNFα-mediated IL-1β synthesis by RAW264.7 cell line. Each value represents the mean±SD. *Represents significant differences between control (PBS) and tested samples at p≤0.05 level. All experiments were performed in triplicate.

Figure 4.
Figure 4.

Effect of CoQ10 and/or glucan addition on IL-1α in plasma in the model of adjuvant arthritis on day 28. Each value represents the mean±SD. *Represents significant differences between control (PBS) and tested samples at p≤0.05 level. All experiments were performed in triplicate.

Next, we evaluated the functionality of blood neutrophils by testing the phagocytosis, oxidative burst, and metabolic activity (Figure 5). Both phagocytosis and oxidative burst were increased due to the AA. Metabolic activity of neutrophils is the percentage of double positive cells – simultaneously phagocytosing and positive for oxidative burst. The immunosuppressive effects of methotrexate were found in all tested parameters, not only when compared to AA, but even to controls. Individual addition of CoQ10 or glucan increased phagocytosis and oxidative burst.

Figure 5.
Figure 5.

Functionality of peripheral blood neutrophils determined on day 7 of induced adjuvant arthritis. Each value represents the mean±SD. *Represents significant differences between control (PBS) and tested samples at p≤0.05 level. All experiments were performed in triplicate.

After evaluation of the effects of tested substances on individual activities, we also tested the effects on cancer. To be sure the effects of these samples truly reflected their potential anticancer properties, we used two different experimental models. With the first, using a well-defined Lewis lung carcinoma model, we found that whereas CoQ10 had only insignificant effects, glucan alone strongly lowered the number of lung metastases. Similarly, a glucan–CoQ10 combination was highly active, but the differences between a combination and glucan alone were not statistically significant (Figure 6). With the second, using a breast cancer model, we monitored the changes in tumor weight. Our results showed identical results (Figure 7).

Discussion

Immunomodulators usually offer systemic effects and the mechanisms of their effects are often unknown. We focused on the hypothesis that glucan and CoQ10 might together offer higher biological effects than individual molecules.

Polysaccharides, such as glucans, have been studied for almost a century. Almost 80 years ago, Shear and coworkers isolated a substance causing tumor necrosis from the culture of Serratia marcescens (30). From this pioneering research, subsequent scientific interest has resulted in over 16,000 studies of glucan activities, making glucan the most studied natural immunomodulator; several in-depth reviews are available (20, 31-34). Most of the glucan studies focused on cancer treatment (35). At the same time, the activities of glucans were found to increase when used together with various substances such as monoclonal antibodies (36) or vitamin C (37, 38). Our own previous research focused on basic immunostimulating capacity of a combination of glucan and resveratrol and showed the significant synergy of these two compounds (39).

Figure 6.
Figure 6.

Effect of tested substances on lung cancer growth in cyclophosphamide treated mice. Cyclophosphamide was injected into mice on day 8 of the inoculation of 1×105 tumor cells, followed by the daily oral doses of individual substances starting 48 hrs after injection of cyclophosphamide. Each value represents the mean±SD. *Represents significant differences between glucan alone and glucan/Se combination at p≤0.05 level.

Figure 7.
Figure 7.

Therapy of Balb/c mice with Ptas64 mammary carcinoma. Data from three independent experiments are shown. For each experiment, groups of three mice were tested for a response to therapy as indicated by the weight of tumors after two weeks of supplementation. Each value represents the mean±SD. *Represents significant differences between control and experimental samples at p≤0.05 level.

Inflammation is one of the leading causes of mortality in the western world. Dietary supplementation with antioxidants is one of the commonly thought solutions, supported by numerous studies (40). CoQ10 is one of the molecules found to have antiinflammatory and antirheumatic properties (41). In addition, significant changes in the levels of CoQ10 were found in a variety of diseases in both animal and human models. Currently, it is not clear if these changes are due to the excessive utilization of CoQ10 or by impairment in biosynthesis (42).

Despite numerous studies showing positive effects of CoQ10 on various biological reactions, the search is on for potential improvement of these effects. One possibility is a combination of CoQ10 with another bioactive molecule. A combination therapy with CoQ10 and additional bioactive substances, such as metformin, showed strong effects against autoimmune diseases including arthritis (43).

We tested peripheral blood neutrophils for changes in phagocytosis. Using synthetic microspheres based on 2-hydroxyethyl methacrylate, known for an extremely low spontaneous adhesion to the cell membrane and therefore minimal false negativity, we found that both glucan and glucan–CoQ10 combination caused a significant increase in phagocytosis, whereas CoQ10 had no effect. The data shown reflect the effects of a 3-day daily oral supplementation with tested substances.

The entire process of phagocytosis and subsequent production and often release of reactive oxygen metabolites are extremely important parts of the defense mechanisms. Neutrophils are heavily involved in most processes of recognition and elimination of invading pathogens. In a model of AA, we found that already seven days after AA induction, AA is accompanied by an increased number of peripheral blood neutrophils. These findings are in agreement with similar effects of CoQ10 found earlier (28).

Anti-inflammatory activity of tested substances was measured using an in vivo experimental model of air pouch, which measures the acute inflammatory response as an increase of cellular infiltration (44). Since nitric oxide represents an important intracellular pro-inflammatory mediator, changes in its level in air pouches were determined after treatment with tested substances. Changes in nitric oxide level production are considered to be linked with anti-inflammatory actions. Both individual substances decreased accumulated nitrite, an index of nitric oxide, but the combination of glucan–CoQ10 was three times more active. From these experiments, we can conclude that both substances possessed significant anti-inflammatory activity, with the highest activity seen with the glucan–CoQ10 combination. In addition, our results showed that incubation with both agents (and their combination in particular) strongly inhibited the levels of inflammatory biomarkers in the presence of TNFα. We presume that these effects were mediated by their antioxidant activity (45, 46).

In the last part of our study, we focused on potential role of CoQ10 and glucan on cancer. Whereas cancer-suppressive effects of glucan are well established in both animal and human models (see reviews by Vannucci et al. (20) and Sima et al. (47)), the possible role of CoQ10 is much less known. From the original study suggesting that it may have a potential for the cancer treatment (48), subsequent studies have focused more on the levels of CoQ10 in cancer patients (49 ,50) than on the therapeutic use (13). Some studies found progress on breast cancer therapy after food supplementation with CoQ10 (51). A combination of CoQ10, nutritional antioxidants, and essential fatty acids resulted in partial remission of breast cancer (52), which led us to the study of a CoQ10–glucan combination. Using two different cancer models, we found that whereas CoQ10 alone has only limited effects on cancer development, the combination with glucan further improves glucan's effects.

To answer the question of possible mechanism/s of action of the combination used in our study is difficult. Glucan works via binding to specific receptors, subsequent activation of several intracellular pathways leading to activation of cells able to kill tumors either directly or via release of bioactive molecules. Much less is known about the action of CoQ10. Experiments focused on evaluation of the mechanism of action are in progress.

In conclusion, CoQ10 has strong anti-inflammatory effects in all experimental models, both in vivo and in vitro. These effects are more pronounced when the CoQ10–glucan combination is used, suggesting that this combination has a potential for further development in anti-inflammatory and anticancer treatment.

Acknowledgements

The Authors are grateful to Ms. Tracey Bender for her editorial help.

Footnotes

  • This article is freely accessible online.

  • Conflicts of Interests

    No conflicts of interests exist for the authors.

  • Received April 5, 2018.
  • Revision received May 11, 2018.
  • Accepted May 15, 2018.

References

  1. ↵
    1. Blackwell TS,
    2. Blackwell TR,
    3. Holden EP,
    4. Christman BW,
    5. Christman JW
    : In vivo antioxidant treatment suppresses nuclear factor-kappa b activation and neutrophilic lung inflammation. J Immunol 157: 1630-1637, 1996.
    OpenUrlAbstract
  2. ↵
    1. Jung HJ,
    2. Park EH,
    3. Lim CJ
    : Evaluation of antiangiogenic, antiinflammatory and antinociceptive activity of coenzyme Q(10) in experimental animals. J Pharm Pharmacol 61: 1391-1395, 2009.
    OpenUrlPubMed
  3. ↵
    1. Chen H,
    2. Tappel AL
    : Protection of vitamin e, selenium, trolox c, ascorbic acid palmitate, acetylcysteine, coenzyme Q0, coenzyme Q10, beta-carotene, canthaxanthin, and (+)-catechin against oxidative damage to rat blood and tissues in vivo. Free Radic Biol Med 18: 949-953, 1995.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Kaliora AC,
    2. Dedoussis GV,
    3. Schmidt H
    : Dietary antioxidants in preventing atherogenesis. Atherosclerosis 187: 1-17, 2006.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Berman M,
    2. Erman A,
    3. Ben-Gal T,
    4. Dvir D,
    5. Georghiou GP,
    6. Stamler A,
    7. Vered Y,
    8. Vidne BA,
    9. Aravot D
    : Coenzyme Q10 in patients with end-stage heart failure awaiting cardiac transplantation: A randomized, placebo-controlled study. Clin Cardiol 27: 295-299, 2004.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Janson M
    : Orthomolecular medicine: The therapeutic use of dietary supplements for antiaging. Clin Interv Aging 1: 261-265, 2006.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Fu X,
    2. Ji R,
    3. Dam J
    : Antifatigue effect of coenzyme Q10 in mice. J Med Food 13: 211-215, 2010.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Brauner H,
    2. Luthje P,
    3. Grunler J,
    4. Ekberg NR,
    5. Dallner G,
    6. Brismar K,
    7. Brauner A
    : Markers of innate immune activity in patients with type 1 and type 2 diabetes mellitus and the effect of the antioxidant coenzyme Q10 on inflammatory activity. Clin Exp Immunol 177: 478-482, 2014.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Lone Y,
    2. Bhide M,
    3. Koiri RK
    : Amelioratory effect of coenzyme Q10 on potential human carcinogen microcystin-lr induced toxicity in mice. Food Chem Toxicol 102: 176-185, 2017.
    OpenUrl
  10. ↵
    1. Bessler H,
    2. Bergman M,
    3. Blumberger N,
    4. Djaldetti M,
    5. Salman H
    : Coenzyme Q10 decreases TNF-alpha and IL-2 secretion by human peripheral blood mononuclear cells. J Nutr Sci Vitaminol (Tokyo) 56: 77-81, 2010.
    OpenUrlPubMed
  11. ↵
    1. Skarlis C,
    2. Gontika M,
    3. Katsavos S,
    4. Velomakis G,
    5. Toulas P,
    6. Anagnostouli M
    : Multiple sclerosis and subsequent human immunodeficiency virus infection: A case wIth the rare comorbidity, focus on novel treatment issues and review of the literature. In Vivo 31: 1041-1046, 2017.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Lee SH,
    2. Park MJ,
    3. Lee SH,
    4. Cho ML
    : Coenzyme Q10 exerts antiinflammatory activity and induces TREG in graft versus host disease. J Med Food 19: 238-244, 2016.
    OpenUrl
  13. ↵
    1. Hodges S,
    2. Hertz N,
    3. Lockwood K,
    4. Lister R
    : CoQ10: Could it have a role in cancer management? Biofactors 9: 365-370, 1999.
    OpenUrlPubMed
  14. ↵
    1. Shih YL,
    2. Wu MF,
    3. Lee CH,
    4. Yeh MY,
    5. Chou J,
    6. Liu JY,
    7. Lu HF,
    8. Huang YP,
    9. Liao NC,
    10. Chung JC
    : Antrodia cinnamomea reduces carbon tetrachloride-induced hepatotoxicity in male Wistar rats. In Vivo 31: 877-884, 2017.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Yang HL,
    2. Lin MW,
    3. Korivi M,
    4. Wu JJ,
    5. Liao CH,
    6. Chang CT,
    7. Liao JW,
    8. Hseu YC
    : Coenzyme Q0 regulates NFkappaB/AP-1 activation and enhances NRF2 stabilization in attenuation of lps-induced inflammation and redox imbalance: Evidence from in vitro and in vivo studies. Biochim Biophys Acta 1859: 246-261, 2016.
    OpenUrl
  16. ↵
    1. Farough S,
    2. Karaa A,
    3. Walker MA,
    4. Slate N,
    5. Dasu T,
    6. Verbsky J,
    7. Fusunyan R,
    8. Canapari C,
    9. Kinane TB,
    10. Van Cleave J,
    11. Sweetser DA,
    12. Sims KB,
    13. Walter JE
    : Coenzyme Q10 and immunity: A case report and new implications for treatment of recurrent infections in metabolic diseases. Clin Immunol 155: 209-212, 2014.
    OpenUrl
  17. ↵
    1. Novak M,
    2. Vetvicka V
    : Beta-glucans, history, and the present: Immunomodulatory aspects and mechanisms of action. J Immunotoxicol 5: 47-57, 2008.
    OpenUrlCrossRefPubMed
    1. Novak M,
    2. Vetvicka V
    : Glucans as biological response modifiers. Endocr Metab Immune Disord Drug Targets 9: 67-75, 2009.
    OpenUrlCrossRefPubMed
    1. Rahar S,
    2. Swami G,
    3. Nagpal N,
    4. Nagpal MA,
    5. Singh GS
    : Preparation, characterization, and biological properties of beta-glucans. J Adv Pharm Technol Res 2: 94-103, 2011.
    OpenUrlCrossRef
  20. ↵
    1. Vannucci L,
    2. Sima P,
    3. Vetvicka V,
    4. Krizan J
    : Lentinan properties in anticancer therapy: A review on the last 12-year literature. Am J Immunol 13: 50-61, 2017.
    OpenUrl
  21. ↵
    1. Richter J,
    2. Svozil V,
    3. Kral V,
    4. Rajnohova Dobiasova L,
    5. Stiborova I,
    6. Vetvicka V
    : Clinical trials of yeast-derived beta-(1,3) glucan in children: Effects on innate immunity. Ann Transl Med 2: 15, 2014.
    OpenUrl
  22. ↵
    1. Verlhac V,
    2. Gabaudan J,
    3. Obach A,
    4. Schüep W,
    5. Hole R
    : Influence of dietary glucan and vitamin C on non-specific and specific immune responses of rainbow trout (Oncorhynchus mykiss). Aquaculture 143: 123-133, 1996.
    OpenUrl
  23. ↵
    1. Vetvicka V,
    2. Vashishta A,
    3. Fuentes M,
    4. Baigorri R,
    5. Garcia-Mina JM,
    6. Yvin JC
    : The relative abundance of oxygen alkyl-related groups in aliphatic domains is involved in the main pharmacological-pleiotropic effects of humic acids. J Med Food 16: 625-632, 2013.
    OpenUrl
  24. ↵
    1. Vetvicka V,
    2. Vetvickova J
    : Combination of glucan, resveratrol and vitamin c demonstrates strong antitumor potential. Anticancer Res 32: 81-87, 2012.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Vetvicka V,
    2. Vetvickova J
    : Immune enhancing effects of wb365, a novel combination of ashwagandha (Withania somnifera) and maitake (Grifola frondosa) extracts. N Am J Med Sci 3: 320-324, 2011.
    OpenUrl
  26. ↵
    1. Vetvicka V,
    2. Fornusek L,
    3. Kopecek J,
    4. Kaminkova J,
    5. Kasparek L,
    6. Vranova M
    : Phagocytosis of human blood leukocytes: A simple micromethod. Immunol Lett 5: 97-100, 1982.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Li W,
    2. Wu X,
    3. Xu X,
    4. Wang W,
    5. Song S,
    6. Liang K,
    7. Yang M,
    8. Guo L,
    9. Zhao Y,
    10. Li R
    : Coenzyme Q10 suppresses TNF-alpha-induced inflammatory reaction in vitro and attenuates severity of dermatitis in mice. Inflammation 39: 281-289, 2016.
    OpenUrl
  28. ↵
    1. Bauerova K,
    2. Paulovicova E,
    3. Mihalova D,
    4. Drafi F,
    5. Strosova M,
    6. Mascia C,
    7. Biasi F,
    8. Rovensky J,
    9. Kucharska J,
    10. Gvozdjakova A,
    11. Ponist S
    : Combined methotrexate and coenzyme q(10) therapy in adjuvant-induced arthritis evaluated using parameters of inflammation and oxidative stress. Acta Biochim Pol 57: 347-354, 2010.
    OpenUrlPubMed
  29. ↵
    1. Vetvicka V,
    2. Yvin JC
    : Effects of marine beta-1,3 glucan on immune reactions. Int Immunopharmacol 4: 721-730, 2004.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Shear MJ,
    2. Turner FC,
    3. Perrault A,
    4. Shovelton T
    : Chemical treatment of tumors. V. Isolation of the hemorrhage-producing fraction from serratia marcescens (Bacillus prodigiosus) culture filtrate. J Natl Cancer Inst 4: 81-97, 1943.
    OpenUrlCrossRef
  31. ↵
    1. de Oliveira Silva V,
    2. Oliveira de Moura N,
    3. Rodrigues de Oliveira LJ,
    4. Peconick AP,
    5. Pereira LJ
    : Promising effects of beta-glucans on metabolism and on the immune responses: Review article. Am J Immunol 13: 62-72, 2017.
    OpenUrl
    1. Meng X,
    2. Liang H,
    3. Luo L
    : Antitumor polysaccharides from mushrooms: A review on the structural characteristics, antitumor mechanisms and immunomodulating activities. Carbohydr Res 424: 30-41, 2016.
    OpenUrl
    1. Nakashima A,
    2. Yamada K,
    3. Iwata O,
    4. Sugimoto R,
    5. Atsuji K,
    6. Ogawa T,
    7. Ishibashi-Ohgo N,
    8. Suzuki K
    : Beta-glucan in foods and its physiological functions. J Nutr Sci Vitaminol (Tokyo) 64: 8-17, 2018.
    OpenUrl
  34. ↵
    1. Vannucci L,
    2. Krizan J,
    3. Sima P,
    4. Stakheev D,
    5. Caja F,
    6. Rajsiglova L,
    7. Horak V,
    8. Saieh M
    : Immunostimulatory properties and antitumor activities of glucans (review). Int J Oncol 43: 357-364, 2013.
    OpenUrlPubMed
  35. ↵
    1. Javmen A,
    2. Nemeikaite-Ceniene A,
    3. Bratchikov M,
    4. Grigiskis S,
    5. Grigas F,
    6. Jonauskiene I,
    7. Zabulyte D,
    8. Mauricas M
    : BETA-glucan from Saccharomyces cerevisiae induces IFN-g production in vivo in BALB/c mice. in Vivo 29: 359-363, 2015.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Yan J,
    2. Allendorf DJ,
    3. Brandley B
    : Yeast whole glucan particle (WGP) beta-glucan in conjunction with antitumour monoclonal antibodies to treat cancer. Expert Opin Biol Ther 5: 691-702, 2005.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Ditteova G,
    2. Velebny S,
    3. Hrckova G
    : Modulation of liver fibrosis and pathophysiological changes in mice infected with Mesocestoides corti (m. Vogae) after administration of glucan and liposomized glucan in combination with vitamin c. J Helminthol 77: 219-226, 2003.
    OpenUrlPubMed
  38. ↵
    1. Eicher SD,
    2. McKee CA,
    3. Carroll JA,
    4. Pajor EA
    : Supplemental vitamin c and yeast cell wall beta-glucan as growth enhancers in newborn pigs and as immunomodulators after an endotoxin challenge after weaning. J Anim Sci 84: 2352-2360, 2006.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Vetvicka V,
    2. Volny T,
    3. Saraswat-Ohri S,
    4. Vashishta A,
    5. Vancikova Z,
    6. Vetvickova J
    : Glucan and resveratrol complex-possible synergistic effects on immune system. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 151: 41-46, 2007.
    OpenUrlPubMed
  40. ↵
    1. Novoselova EG,
    2. Lunin SM,
    3. Novoselova TV,
    4. Khrenov MO,
    5. Glushkova OV,
    6. Avkhacheva NV,
    7. Safronova VG,
    8. Fesenko EE
    : Naturally occurring antioxidant nutrients reduce inflammatory response in mice. Eur J Pharmacol 615: 234-240, 2009.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Bauerova K,
    2. Kucharska J,
    3. Mihalova D,
    4. Navarova J,
    5. Gvozdjakova A,
    6. Sumbalova Z
    : Effect of coenzyme Q(10) supplementation in the rat model of adjuvant arthritis. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 149: 501-503, 2005.
    OpenUrlPubMed
  42. ↵
    1. Folkers K,
    2. Yamagami T,
    3. Littarru GP
    1. Littarru GP,
    2. Lippa S,
    3. Oradei A,
    4. Fiorni RM,
    5. Mazzanti L
    : Metabolic and diagnostic implications of blood COQ10 levels. In: Biomedical and clinical aspects of coenzyme Q: Proceedings. Folkers K, Yamagami T, Littarru GP (eds.). Elsevier Science Ltd: Amsterdam, pp. 167-178, 1991.
  43. ↵
    1. Jhun J,
    2. Lee S,
    3. Kim SY,
    4. Na HS,
    5. Kim EK,
    6. Kim JK,
    7. Jeong JH,
    8. Park SH,
    9. Cho ML
    : Combination therapy with metformin and coenzyme Q10 in murine experimental autoimmune arthritis. Immunopharmacol Immunotoxicol 38: 103-112, 2016.
    OpenUrl
  44. ↵
    1. Nathan C
    : Points of control in inflammation. Nature 420: 846-852, 2002.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Abdollahzad H,
    2. Aghdashi MA,
    3. Asghari Jafarabadi M,
    4. Alipour B
    : Effects of coenzyme Q10 supplementation on inflammatory cytokines (TNF-alpha, IL-6) and oxidative stress in rheumatoid arthritis patients: A randomized controlled trial. Arch Med Res 46: 527-533, 2015.
    OpenUrl
  46. ↵
    1. Schmelzer C,
    2. Lorenz G,
    3. Lindner I,
    4. Rimbach G,
    5. Niklowitz P,
    6. Menke T,
    7. Doring F
    : Effects of coenzyme Q10 on TNF-alpha secretion in human and murine monocytic cell lines. Biofactors 31: 35-41, 2007.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Sima P,
    2. Vannucci L,
    3. Vetvicka V
    : Glucan and cancer: Historical prospective. Canc Transl Med 1: 209-214, 2015.
    OpenUrl
  48. ↵
    1. Folkers K
    : The potential of coenzyme q 10 (nsc-140865) in cancer treatment. Cancer Chemother Rep 4: 19-22, 1974.
    OpenUrl
  49. ↵
    1. Folkers K,
    2. Osterborg A,
    3. Nylander M,
    4. Morita M,
    5. Mellstedt H
    : Activities of vitamin Q10 in animal models and a serious deficiency in patients with cancer. Biochem Biophys Res Commun 234: 296-299, 1997.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Portakal O,
    2. Ozkaya O,
    3. Erden Inal M,
    4. Bozan B,
    5. Kosan M,
    6. Sayek I
    : Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients. Clin Biochem 33: 279-284, 2000.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Lockwood K,
    2. Moesgaard S,
    3. Yamamoto T,
    4. Folkers K
    : Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases. Biochem Biophys Res Commun 212: 172-177, 1995.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Lockwood K,
    2. Moesgaard S,
    3. Hanioka T,
    4. Folkers K
    : Apparent partial remission of breast cancer in ‘high risk’ patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Mol Aspects Med 15(Suppl): s231-240, 1994.
    OpenUrl
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Combination Therapy with Glucan and Coenzyme Q10 in Murine Experimental Autoimmune Disease and Cancer
VACLAV VETVICKA, JANA VETVICKOVA
Anticancer Research Jun 2018, 38 (6) 3291-3297; DOI: 10.21873/anticanres.12594
Reddit logo Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords