Coenzyme Q and cancer prevention -
Robert V. Cooney ; Robert V. Adrian A. Franke ; Adrian A. Yurii B. Shvetsov ; Yurii B. Christian P. Caberto ; Christian P.
Lynne R. Wilkens ; Lynne R. Loïc Le Marchand ; Loïc Le Marchand. Brian E. Henderson ; Brian E. Laurence N. Kolonel ; Laurence N. Marc T. Goodman Marc T. Received: April 15 Revision Received: June 15 Accepted: June 25 Online ISSN: Cancer Epidemiol Biomarkers Prev 19 9 : — Article history Received:.
Revision Received:. Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Table 1. View Large. Table 2. P for trend §. Table 3. No potential conflicts of interest were disclosed. Search ADS. Activities of vitamin Q10 in animal models and a serious deficiency in patients with cancer.
An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences.
Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients. Effects of menopause and hormone replacement therapy on serum levels of coenzyme Q10 and other lipid-soluble antioxidants. Coenzyme Q10 in human blood: native levels and determinants of oxidation during processing and storage.
Elevated plasma γ-tocopherol and decreased α-tocopherol in men are associated with inflammatory markers and decreased plasma OH vitamin D. Plasma sex hormone concentrations and breast cancer risk in an ethnically diverse population of postmenopausal women: the Multiethnic Cohort Study.
Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. Postmenopausal hormone therapy and breast cancer risk: the Multiethnic Cohort. Antioxidant level and redox status of coenzyme Q10 in the plasma and blood cells of children with diabetes mellitus type 1.
γ-Tocopherol, but not α-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats. View Metrics. Citing articles via Web Of Science CrossRef Email alerts Article Activity Alert.
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Nahas R. Complementary and alternative medicine approaches to blood pressure reduction: An evidence-based review. Can Fam Physician. Ochiai A, Itagaki S, Kurokawa T, Kobayashi M, Hirano T, Iseki K. Improvement in intestinal coenzyme q10 absorption by food intake.
Yakugaku Zasshi. Ostrowski RP. Effect of coenzyme Q 10 on biochemical and morphological changes in experimental ischemia in the rat brain. Brain Res Bull. Palan PR, Connell K, Ramirez E, Inegbenijie C, Gavara RY, Ouseph JA, Mikhail MS.
Effects of menopause and hormone replacement therapy on serum levels of coenzyme Q10 and other lipid-soluble antioxidants. Quinzii CM, Dimauro S, Hirano M. Human coenzyme q 10 deficiency. Neurochem Res. Raitakari OT, McCredie RJ, Witting P, Griffiths KA, Letter J, Sullivan D, Stocker R, Celermajer DS.
Coenzyme Q improves LDL resistance to ex vivo oxidation but does not enhance endothelial function in hypercholesterolemic young adults. Free Radic Biol Med. Rakel D. Rakel: Integrative Medicine. Philadelphia, PA: Elsevier Saunders; Rosenfeldt FL, Haas SJ, Krum H, Hadj A, Ng K, Leong JY, Watts GF.
Conenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens. Rosenfeldt F, Hilton D, Pepe S, Krum H. Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure.
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Coenzyme Q10 CoQ10; Ubiquinone. Uses Some studies suggest that coenzyme Q10 supplements, either by themselves or in with other drug therapies, may help prevent or treat the following conditions: After Heart Attack One clinical study found that people who took daily CoQ10 supplements within 3 days of a heart attack were less likely to have subsequent heart attacks and chest pain.
Heart failure HF There is evidence that CoQ10 may help treat heart failure when combined with conventional medications.
High blood pressure Several clinical studies involving small numbers of people suggest that CoQ10 may lower blood pressure. High cholesterol People with high cholesterol tend to have lower levels of CoQ10, so CoQ10 has been proposed as a treatment for high cholesterol, but scientific studies are lacking.
Diabetes CoQ10 supplements may improve heart health and blood sugar and help manage high blood pressure in people with diabetes. Heart damage caused by chemotherapy Several clinical studies suggest that CoQ10 may help prevent heart damage caused by certain chemotherapy drugs, adriamycin, or other athracycline medications.
Heart surgery Clinical research indicates that introducing CoQ10 prior to heart surgery, including bypass surgery and heart transplantation, can reduce damage caused by free radicals, strengthen heart function, and lower the incidence of irregular heart beat arrhythmias during the recovery phase.
Gum Periodontal disease Gum disease is a common problem that causes swelling, bleeding, pain, and redness of the gums. A large number of epidemiological studies have reported an inverse relationship between the blood level of β-carotene and lung cancer risk 54 , The incidence of non-melanocytic skin cancer was inversely related to the serum level of β-carotene In addition, β-carotene was found to be photoprotective against UV-induced carcinogenesis However, a study demonstrated that β-carotene-supplemented semi-defined diets not only provided no photoprotective effect, but also significantly exacerbated UV-induced carcinogenesis In addition, smokers supplemented with β-carotene demonstrated a significantly higher incidence of lung cancer compared with smokers who were not taking β-carotene as a supplement 59 , Epidemiological studies have demonstrated an association between higher incidence of lung cancer and β-carotene intake 50 , The effect of β-carotene on the initiation and development of cancers may be divergent in different cancers To the best of our knowledge no research has been done on the effect of β-carotene on the proliferation and invasiveness of human malignant melanoma cells.
To the best of our knowledge the effect of β-carotene on the cytotoxicity of BRAF inhibitors has not been investigated either. Since cancer cells perform high-level metabolic activity and suffer from more oxidative stress 63 , antioxidants could potentially promote the growth and progression of cancers by mopping up free radicals from cancer cells.
In fact, our previous research has demonstrated that antioxidant vitamin C exerted a stimulatory effect at physiological concentration on the growth and metastasis of human malignant melanoma In the present study, we hypothesized that the antioxidants CoQ and β-carotene have an effect on the growth and invasiveness of human malignant melanoma cells.
In addition, in a previous study our lab demonstrated that the BRAF kinase inhibitor vemurafenib, an FDA-approved antimelanoma drug, increased the oxidative stress in human malignant melanoma cells 64 ; thus antioxidants may interfere with the cytotoxic effect of vemurafenib on melanoma cells by scavenging free radicals.
Hence, the present study aimed to determine the effect of CoQ and β-carotene on the growth, migration and invasion and apoptosis induction of human malignant melanoma cell lines, and also on the cytotoxicity of emurafenib on human malignant melanoma cells.
Τhe present study aimed to better understand the biological effects and working mechanism of the antioxidants CoQ and β-carotene on malignant melanoma so that clinicians can decide whether adding antioxidant supplements to the cancer treatment regimen is a viable option.
Vemurafenib PLX; cat. S was purchased from Selleck Chemicals. CoQ10 cat. C and β-carotene cat. C were purchased from Sigma-Aldrich; Merck KGaA. SK-MEL PLX sensitive and A PLX resistant human melanoma cell lines were purchased from the American Type Culture Collection ATCC.
SK-MEL and A were cultured in Eagle's Minimum Essential Medium EMEM; Thermo Fisher Scientific Inc. and Dulbecco's Modified Eagle's medium DMEM; Thermo Fisher Scientific Inc. and 0. and incubated for 12 h to allow the cells to attach. To test the effect of the CoQ10 on cell viability, the cells in the experimental groups were treated with CoQ10 at final concentrations of 1, 5 and 10 µM, respectively.
The cells in control groups were treated with the drug vehicle dimethyl sulfoxide DMSO Fisher Bioreagents; Thermo Fisher Scientific Inc.
To test the efficacy of CoQ10 on the cytotoxicity of PLX against melanoma cell proliferation, the SK-MEL and A cells were treated with PLX at 2 and 20 µM, respectively, together with CoQ10 at 1, 5 and 10 µM.
The cells in the control groups were treated with the drug vehicle dimethyl sulfoxide DMSO Fisher Bioreagents; Thermo Fisher Scientific Inc. After incubation for 48 h, 10 µM MTS 3- 4,5-dimethylthiazolyl 3-carboxymethoxyphenyl 4-sulfophenyl -2H tetrazolium reagent Promega Corporation was added into each well and incubated for 3 h at 37°C.
The absorbance of solubilized dye was measured by a microplate reader BioTek Instruments Inc. at nm. Three independent experiments were performed and the results were reported as means ± SD.
Then the layer of cells was scraped with a µl micropipette tip to create a wound. Plates were washed with Hanks' Balanced Salt Solution HBSS; Sigma-Aldrich; Merck KGaA and replaced with fresh serum free medium.
The assay was performed in 8 groups: i Group 1 was the control group, which was treated with drug vehicle DMSO ; ii groups 2, 3, and 4 were treated with CoQ10 or β-carotene at final concentrations of 1, 5 and 10 µM, respectively; iii group 5 was treated with 2 µM PLX alone; and iv groups 6, 7, and 8 were treated with PLX at a final concentration of 2 µM and CoQ10 or β-carotene at final concentrations of 1, 5 and 10 µM, respectively.
The images of the wounds were captured at 0 and 24 h under an inverted light microscope magnification, × and the average wound distance was calculated using ImageJ software v. Matrigel-precoated well Transwell inserts cat.
were used. A 3×10 4 cells were resuspended in µl serum-free Eagle's minimum essential medium in the upper chamber of a well plate. The assay was performed in 8 groups: i Group 1 was the control group, which was treated with drug vehicle DMSO ; ii groups 2, 3, and 4 were treated with β-carotene at final concentrations of 1, 5 and 10 µM, respectively; iii groups 5, 6, and 7 were treated with PLX at a final concentration of 2 µM and β-carotene at final concentrations of 1, 5, and 10 µM, respectively; and iv group 8 was treated with 2 µM PLX alone.
Non-migrated cells were scraped off using cotton swabs and migrated cells were counted under the inverted light microscope magnification, × Apoptosis was examined using an Annexin V-FITC-propidium iodide PI dual staining kit BioLegend Inc.
followed by flow cytometry analysis according to the manufacturer's instructions. The assay was performed in 8 groups: i Group 1 was the control group which was treated with drug vehicle DMSO ; ii groups 2, 3, and 4 were treated with CoQ10 at final concentrations of 1, 5 and 10 µM, respectively; iii groups 5, 6, and 7 were treated with PLX at a final concentration of 2 µM and Coenzyme Q10 at final concentrations of 1, 5 and 10 µM, respectively; and iv group 8 was treated with 2 µM PLX alone.
After 24 h, A and SK-MEL were harvested by trypsinization, washed with ice-cold cell staining buffer Biolegend Inc. Cell suspension was stained with Annexin V-FITC and PI and analyzed by the Accuri C6 Flow Cytometer System BD Biosciences.
Both early and late stages of apoptotic cells were counted using associated software CytExpert v. After a 48 h treatment, A cells were trypsinized and washed 3 times with PBS and then lysed in a lysis buffer for 30 min at 4°C. The proteins were extracted in the supernatant after centrifugation at 14, g for 20 min at 4°C and the concentration of protein was detected using Bio-Rad protein assay reagent Bio-Rad Laboratories Inc.
The protein was transferred to a nitrocellulose membrane at mA for 1 h in the transfer buffer. The membrane was then rinsed 3 times with TBST, and subsequently immunoblotted with primary antibodies for rabbit anti-GAPDH ,; cat.
at 4°C overnight. Signals were developed by incubating with the horse radish peroxidase HRP -linked secondary antibody ,; cat. for 2 h at room temperature. GAPDH was used as the internal loading control. Subsequently, development was performed using the Clarity TM Western ECL Substrate Bio-Rad Laboratories Inc.
for 5 min. The intensity of the signals was determined by the FluorChem TM E system Protein Simple. ImageJ v. All values are represented as mean ± standard deviation SD from at least three independent experiments, and were subjected to one-way analysis of variance ANOVA and compared by the post hoc Tukey's HSD test using SAS University edition SAS Institute Inc.
MTS assay was used to determine the cytotoxic effect of CoQ10 and β-carotene in 2 malignant melanoma cell lines: SK-MEL and A In the SK-MEL cell line, which is vemurafenib sensitive, CoQ10 decreased the cell viability and displayed cytotoxicity at 5 and 10 µM, but did not affect the cytotoxicity of PLX Fig.
In A, which is a vemurafenib-resistant cell line, CoQ10 did not display cytotoxicity Fig. However, CoQ10 increased the cytotoxicity of PLX at 1, 5 and 10 µM Fig. In both SK-MEL and A cell lines, β-carotene did not display cytotoxicity Fig.
However, β-carotene alleviated the cytotoxicity of PLX in both cell lines Fig. CoQ10 and β-carotene alleviate the cytotoxicity of PLX against melanoma cells. A and B Effects of CoQ10 and C and D β-carotene on the cell viability of SK-MEL and A melanoma cells and the effect of these 2 antioxidants on the cytotoxicity of PLX against SK-MEL and A melanoma cells were determined by the MTS assay after 48 h of treatment.
Each experiment was repeated three times with quadruplicate reactions in each treatment. combined treatment groups PLX and CoQ10 group or PLX and β-carotene group.
CoQ10, coenzyme Q10; PLX, vemurafenib. SK-MEL and A migration was examined using the wound healing assay. β-carotene inhibited the migration of SK-MEL cells Fig.
Notably, β-carotene alleviated the inhibitory effect of PLX on the migration of both SK-MEL Fig. CoQ10 inhibited the migration of both SK-MEL Fig. In contrast to β-carotene, CoQ10 at 10 µM enhanced the inhibition of SK-MEL cell migration by PLX Fig.
CoQ10 and β-carotene inhibit melanoma cell migration, but display different effects on the migration inhibition caused by PLX.
A Representative images of the effect of β-carotene on cell migration and on the inhibitory effect of PLX on cell migration of A SK-MEL and B A melanoma cells. C Representative images of the effect of CoQ10 on cell migration and on the inhibitory effect of PLX on cell migration of C SK-MEL and D A melanoma cells.
E Quantification of migration index of A. F Quantification of migration index of B. G Quantification of migration index of C. H Quantification of migration index of D. Since it was reported that β-carotene inhibited lung metastasis of murine melanoma in vivo 53 and inhibited migration and invasion of human hepatocarcinoma cells in vitro 65 , based on these findings the present study examined the effects of β-carotene on the invasive ability of A human melanoma cells and on the inhibitory effect of PLX on cell invasion using a Matrigel-coated Transwell cell invasion assay.
Notably, β-carotene alleviated the inhibitory effect of PLX on A melanoma cell invasion in a dose-dependent manner Fig. β-carotene inhibits cell invasion and alleviates the inhibitory effect of PLX on cell invasion. B Migrated cell numbers in the control group and different treatment groups.
combined treatment groups PLX and β-carotene group. To determine whether CoQ10 and β-carotene induce apoptosis and affect apoptosis induced by PLX, SK-MEL and A cells were treated with CoQ10 or β-carotene alone, PLX alone, the combination of PLX and CoQ10, or a combination of PLX and β-carotene.
CoQ10 at 10 µM inhibited the apoptosis induced by PLX in A Fig. Notably, CoQ10 alone inhibited the apoptosis in SK-MEL cells Fig. Similarly, β-carotene at 10 µM protected A Fig. However, β-carotene alone did not inhibit the apoptosis in SK-MEL cells Fig. CoQ10 and β-carotene protect cells from apoptosis induced by PLX.
A Apoptosis of A cell treated with coenzyme Q10 alone, PLX alone, a combination of PLX with coenzyme Q10, or DMSO vehicle; B Quantification of apoptosis rate. C Apoptosis of SK-MEL cells treated with coenzyme Q10 alone, PLX alone, a combination of PLX with coenzyme Q10, or DMSO vehicle. D Quantification of apoptosis rate of panel C.
E Apoptosis of A cell treated with β-carotene alone, PLX alone, a combination of PLX with β-carotene, or DMSO vehicle. F Quantification of apoptosis rate of panel E. G Apoptosis of SK-MEL cells treated with β-carotene alone, PLX alone, a combination of PLX with β-carotene, or DMSO vehicle.
H Quantification of apoptosis rate shown in panel G. PLX, vemurafenib; PI, propidium iodide. Since the inhibitory effect of CoQ10 on the signaling pathway has been more established, the present study examined the effect of β-carotene on the Ras-Raf-Mek-Erk signaling pathway.
Ras-Raf-Mek-Erk is an important intracellular cell growth signaling pathway and serves critical roles in cancer initiation and development In addition, β-carotene affects the cytotoxicity of veramufenib Fig. Based on these findings the present study investigated the effect of β-carotene on activation of the Ras-Raf-Mek-Erk signaling pathway.
A cells, which harbor a BRAF activating mutation and are melanoma resistant, were treated with β-carotene alone, PLX alone, the combination of PLX and β-carotene, and DMSO vehicle. After 48 h incubation, western blotting demonstrated that β-carotene had no effect on BRAF or ERK expression Fig.
β-carotene works synergistically with PLX to suppress the Ras-Raf-Mek-Erk pathway. A cells were treated with β-carotene at concentrations of 0, 1, 5 and 10 µM in absence or absence of PLX 2 µM , and the expression levels of A activated form of Braf phospho-Braf and Erk phosphor-Erk and B non-activated Braf and Erk were analyzed by western blotting.
Antioxidants are molecules that scavenge free radicals including ROS, and thus, relieve the oxidative stress of cells An insufficient level of antioxidants causes increased oxidative stress that is closely involved in aging and numerous diseases including cancers Specifically, antioxidants affect tumor initiation and development through quenching carcinogen activation, reducing DNA oxidation, switching of growth-related signal transduction pathways, inducing cell cycle arrest and inhibiting cell migration and invasion Hence, it is generally believed that taking antioxidant supplementation is beneficial for the prevention and treatment of cancers Numerous research articles advocated antioxidants as cancer fighters 70 — 72 and reported that high doses of dietary antioxidants often inhibit the growth of cancer cells without affecting the growth of normal cells 71 , A population-based prospective cohort study demonstrated that the use of antioxidants vitamin E and C in the first six months of diagnosis significantly reduced the mortality and recurrence of invasive breast cancer Antioxidants have been used as beneficial adjuncts to the conventional cancer therapy in clinical studies 74 , However, increasing evidence has demonstrated that antioxidants are not necessarily beneficial in combating cancers.
For example, it has been reported that antioxidants stimulated cell growth in parotid acinar cells In addition, the use of antioxidants vitamin E and β-carotene concurrently with radiotherapy in head and neck cancer patients significantly increased recurrence and cancer-specific mortality Hence, whether the use of antioxidants in cancer prevention and treatment is recommendable and whether antioxidants exert a synergistic or antagonistic effect with chemotherapy deserves close scrutiny.
The present study examined the effects of two antioxidants, CoQ10 and β-carotene, on the viability, migration, invasion, apoptosis, and intracellular signaling of human malignant melanoma cells.
As our previous study demonstrated that vemurafenib increased the oxidative stress in human malignant melanoma cells 33 , the present study hypothesized that CoQ10 and β-carotene can affect the cytotoxicity of vemurafenib by modulating oxidative stress and its downstream effects.
The present study used a venurafenib-resistant melanoma cell line A to examine whether the combination of antioxidants with vemurafenib can produce stronger cytotoxicity against resistant cell lines. CoQ10 is a free radical-scavenging antioxidant due to its capacity to act as both a two-electron carrier and a one-electron carrier Since no large-scale strictly-controlled clinical trials of coenzyme Q10 in cancer treatment have been done, the association between coenzyme Q10 and cancers is not well understood Research has demonstrated that an imbalance in the antioxidant system can be detected in melanoma cells and in a percentage of normal melanocytes from patients with melanoma 78 , and low plasma level of CoQ10 may be a prognostic factor for melanoma progression Due to the low concentration of coenzyme Q10 in melanoma cell lines, and in sera of patients with melanoma, CoQ10 was used in combination with an optimized dose of recombinant interferon α-2b in a 3-year trial, which demonstrated that this combination significantly reduced the recurrence rate It is also known that mg per day is a common dosage of commercial products of coenzyme Q10 Published research used coenzyme Q10 at concentrations from 5—60 µM 64 , 82 , The present study used CoQ10 at concentrations of 1, 5 and 10 µM that are achievable in the plasma of CoQ10 supplement-consuming individuals.
Hong et al 49 reported that coenzyme Q10 did not suppress the BRAF VE melanoma cell line. However, by examining the effect of coenzyme Q10 on the viability of two human malignant melanoma cell lines in the present study, it was found that CoQ10 significantly reduced the viability of SK-MEL cells, which is a PLX-sensitive melanoma cell line.
In the present study for the A cell line, which is a PLX-resistant cell line, CoQ10 alone did not display cytotoxicity. However, it increased the cytotoxicity of the FDA-approved Braf inhibitor vemurafenib. The findings of the present study support the notion that CoQ10 can potentially be a good adjunct to targeted chemotherapy or immunotherapy against melanoma.
The present study also demonstrated that CoQ10 significantly reduced the migration of both SK-MEL and A cells. To the best of our knowledge, the present study is the first to have reported the inhibitory effect of CoQ10 on the migration of cancer cells. It has been previously reported that a functional dietary supplement containing CoQ10 branched-chain amino acids and L-carnitine completely inhibited the metastasis of melanoma to the lung In addition, exogenous CoQ10 reduced matrix metalloproteinases 2 MMP-2 activity in a breast cancer cell line MCF-7 , suggesting the importance of coenzyme Q10 on cell invasion effector molecules Hence, CoQ10 may inhibit metastasis of melanoma by directly inhibiting cell migration and reducing MMP-2 activity that helps melanoma cells break through the intracellular matrix facilitating metastasis.
The present study also examined the effect of CoQ10 on the induction of apoptosis that serves vital roles in tumor survival and progression. The present study demonstrated that CoQ10 significantly reduced the percentage of apoptotic cells.
In addition, CoQ10 alleviated the apoptosis induced by vemurafenib in both A and SK-MEL cells. This finding is in concert with previous reports that demonstrated that CoQ10 protects cells from undergoing apoptosis induced by cytotoxic chemicals in both cancerous 86 and non-cancerous cells
Chris Coenzyme Q and cancer preventionHyung-Suk YoonWei ZhengCoenzyme Q and cancer prevention WuPrevnetion A. Franke Cosnzyme, William J. Blot pprevention, Xiao-Ou ShuQiuyin Convenient weight loss Abstract Circulating levels of coenzyme Q10 and lung cancer risk. Background: Coenzyme Q10 CoQ10 is an ubiquitous molecule in living organisms that serves as a cofactor in energy production via the electron-transport chain ETC. Research has previously shown that deficiencies in CoQ10 can result in a variety of detrimental outcomes including cardiovascular disease and neurological disorders. Coenxyme information is produced and provided Hyperglycemic crisis in type diabetes the National Cancer Institute NCI. The canver in this topic may have changed since it was written. gov or call CANCER. This cancer information summary provides an overview of the use of coenzyme Q 10 in cancer therapy. The summary includes a history of coenzyme Q 10 research, a review of laboratory studies, and data from investigations involving human subjects.
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