ubiquinone and Skin-Neoplasms

Early surgical intervention remains the most successful therapy for melanoma. Despite better outcomes observed in soft tissue and lymph node metastases, the results of pharmacological therapies are still disappointing. Currently, there is no standard adjuvant therapy for melanoma. Low concentrations of coenzyme Q10 have been demonstrated in melanoma cell lines and in sera of melanoma patients. These data and the results of clinical trials of patients with other advanced cancers prompted this study of the long-term administration of an optimized dose of recombinant interferon alpha-2b and coenzyme Q10 to patients with stage I and II melanoma. A 3-year trial envisaging uninterrupted treatment with low-dose recombinant interferon alpha-2b (9 000 000 000 IU weekly) administered twice daily and coenzyme Q10 (400 mg/day) was conducted in patients with stage I and II melanoma (American Joint Committee on Cancer criteria 2002) and surgically removed lesions. Treatment efficacy was evaluated as incidence of recurrences at 5 years. All patients completed the treatment and the follow-up. Significantly different rates of disease progression were observed in the interferon+coenzyme Q10 and the interferon group for both stages. No patient withdrew from the study owing to side effects. Long-term administration of an optimized dose of recombinant interferon alpha-2b in combination with coenzyme Q10 seemed to induce significantly decreased rates of recurrence and had negligible adverse effects. A survival study could not be undertaken owing to the small patient sample and the short duration of follow-up.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Coenzymes; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Logistic Models; Male; Melanoma; Middle Aged; Neoplasm Staging; Recombinant Proteins; Recurrence; Skin Neoplasms; Time Factors; Treatment Outcome; Ubiquinone; Vitamins

Cutaneous melanoma is the deadliest type of skin cancer, although it accounts for a minority of all skin cancers. Oxidative stress is involved in all stages of melanomagenesis and cutaneous melanoma can sustain a much higher load of Reactive Oxygen Species (ROS) than normal tissues. Melanoma cells exploit specific antioxidant machinery to support redox homeostasis. The enzyme UBIA prenyltransferase domain-containing protein 1 (UBIAD1) is responsible for the biosynthesis of non-mitochondrial CoQ10 and plays an important role as antioxidant enzyme. Whether UBIAD1 is involved in melanoma progression has not been addressed, yet. Here, we provide evidence that UBIAD1 expression is associated with poor overall survival (OS) in human melanoma patients. Furthermore, UBIAD1 and CoQ10 levels are upregulated in melanoma cells with respect to melanocytes. We show that UBIAD1 and plasma membrane CoQ10 sustain melanoma cell survival and proliferation by preventing lipid peroxidation and cell death. Additionally, we show that the NAD(P)H Quinone Dehydrogenase 1 (NQO1), responsible for the 2-electron reduction of CoQ10 on plasma membranes, acts downstream of UBIAD1 to support melanoma survival. By showing that the CoQ10-producing enzyme UBIAD1 counteracts oxidative stress and lipid peroxidation events in cutaneous melanoma, this work may open to new therapeutic investigations based on UBIAD1/CoQ10 loss to cure melanoma.

Topics: Antioxidants; Cell Death; Dimethylallyltranstransferase; Humans; Lipid Peroxidation; Melanoma; Melanoma, Cutaneous Malignant; Skin Neoplasms; Ubiquinone

Low-molecular-weight antioxidants are some of the most efficient agents of the skin defense mechanism against environmental factors, such as cosmic rays, smoke, and pollutants. The total skin concentrations of hydrophilic ascorbic and uric acids, as well as lipophilic α-tocopherol, β-carotene, and ubiquinol-10 antioxidants were determined by an HPLC-EC detector from 18 biopsies of human nonmelanoma skin carcinomas and 18 biopsies from skin areas adjacent to carcinomas. No significant differences in the concentrations of lipophilic antioxidants in both carcinomas and normal-looking skin areas adjacent to carcinomas were observed. On the contrary, ascorbic and uric acid concentrations were found to be 18 and 36% lower in carcinomas than in normal-looking skin areas, respectively. No statistical significance was observed between antioxidant concentrations and age, sex, phototype, profession, site of tumor, frequency, and time of UV light exposure either. Accordingly the antioxidant concentrations in both cancerous skin and adjacent normal-looking areas were found to be much higher than in normal skin, in contrast to literature data.

Topics: Adult; Aged; Aged, 80 and over; alpha-Tocopherol; Antioxidants; Ascorbic Acid; beta Carotene; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Male; Middle Aged; Molecular Weight; Skin; Skin Neoplasms; Ubiquinone; Uric Acid

Topics: Animals; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Mutation, Missense; Neurilemmoma; Neurofibromatoses; Skin Neoplasms; Ubiquinone

Topics: Animals; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Mutation, Missense; Neurilemmoma; Neurofibromatoses; Skin Neoplasms; Ubiquinone

Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease.. We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family.. We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells.. Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792.

Topics: Amino Acid Sequence; Animals; Base Sequence; Blotting, Western; Cell Line; Cells, Cultured; Chromosomal Proteins, Non-Histone; DNA Mutational Analysis; DNA-Binding Proteins; Family Health; Gene Knockdown Techniques; Genetic Complementation Test; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; In Situ Hybridization, Fluorescence; Molecular Sequence Data; Mutation, Missense; Neurilemmoma; Neurofibromatoses; Pedigree; Rats; Reactive Oxygen Species; Saccharomyces cerevisiae; Sequence Homology, Amino Acid; Skin Neoplasms; SMARCB1 Protein; Transcription Factors; Ubiquinone

Abnormally low plasma levels of coenzyme Q10 (CoQ10) have been found in patients with cancer of the breast, lung, or pancreas.. A prospective study of patients with melanoma was conducted to assess the usefulness of CoQ10 plasma levels in predicting the risk of metastasis and the duration of the metastasis-free interval.. Between January 1997 and August 2004, plasma CoQ10 levels were measured with high-performance liquid chromatography in 117 consecutive melanoma patients without clinical or instrumental evidence of metastasis according to American Joint Committee on Cancer criteria and in 125 matched volunteers without clinically suspect pigmented lesions. Patients taking CoQ10 or cholesterol-lowering medications and those with a diagnosis of diabetes mellitus were excluded from the study. Multiple statistical methods were used to evaluate differences between patients and control subjects and between patients who did (32.5%) and did not (67.5%) develop metastases during follow-up.. CoQ10 levels were significantly lower in patients than in control subjects (t test: P < .0001) and in patients who developed metastases than in the metastasis-free subgroup (t test: P < .0001). Logistic regression analysis indicated that plasma CoQ10 levels were a significant predictor of metastasis (P = .0013). The odds ratio for metastatic disease in patients with CoQ10 levels that were less than 0.6 mg/L (the low-end value of the range measured in a normal population) was 7.9, and the metastasis-free interval was almost double in patients with CoQ10 levels 0.6 mg/L or higher (Kaplan-Meier analysis: P < .001).. A study with a larger sample, which is currently being recruited, and a longer follow-up will doubtlessly increase the statistical power and enable survival statistics to be obtained.. Analysis of our findings suggests that baseline plasma CoQ10 levels are a powerful and independent prognostic factor that can be used to estimate the risk for melanoma progression.

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; Biomarkers, Tumor; Coenzymes; Disease Progression; Humans; Logistic Models; Melanoma; Middle Aged; Prognosis; Prospective Studies; Skin Neoplasms; Ubiquinone

In order to evaluate the free radical defense systems of melanocytes and their possible correlation with melanoma, we have studied in cultured normal human melanocytes (20), normal melanocytes from melanoma patients (15), and melanoma cells (40) the fatty acid pattern of membrane phospholipids as a target of peroxidative damage and the superoxide dismutase and catalase activities, vitamin E, and ubiquinone levels as intracellular antioxidants. Cells were cultured in the same medium and analyzed at III or IV passage. Compared to the values obtained in normal human melanocytes, melanoma cells showed on average: a) higher levels of polyunsaturated fatty acids, b) increased superoxide dismutase and decreased catalase activities, higher vitamin E, and lower ubiquinone levels. Among the normal melanocytes from melanoma patients studied, two groups were differentiated: a) cultures (7) with enzymatic and non-enzymatic antioxidants level similar to those of normal human melanocytes; b) cultures (8) with antioxidant patterns similar to those observed in melanoma cells. Polyunsaturated fatty acids were also increased in the latter group. The results indicate that in melanoma cells and in a percentage of normal melanocytes from melanoma patients, an imbalance in the antioxidant system can be detected that can lead to endogenous generation of reactive oxygen species and to cellular incapability of coping with exogenous peroxidative attacks. These alterations could be correlated with the malignant transformation of cells and with the progression of the disease.

Topics: Adult; Antioxidants; Catalase; Fatty Acids, Unsaturated; Humans; Melanocytes; Melanoma; Middle Aged; Reference Values; Skin Neoplasms; Superoxide Dismutase; Ubiquinone; Vitamin E

Canventol, a synthetic compound, is a new inhibitor of tumor promotion on mouse skin by okadaic acid. We previously reported that canventol acts by inhibiting both protein isoprenylation and tumor necrosis factor-alpha (TNF-alpha) release. In this study we examined the potencies of 10 newly synthesized canventol analogs through their effect on mevalonate metabolism, and then examined 3 representative analogs for inhibition of protein isoprenylation. Since canventol in vitro did not directly inhibit farnesyl protein transferase or geranylgeranyl protein transferase-I, the effects of canventol and its synthetic analogs on the fate of [3H]mevalonate in cells were studied. Canventol at 500 microM changed the ratio of newly synthesized sterols (cholesterol and lathosterol) to ubiquinones from 0.7 to 8.2 in NIH/3T3 cells which had previously been labeled with [3H]mevalonate, suggesting that the altered pattern of mevalonate metabolism is associated with inhibition of protein isoprenylation in the cells. We named this ratio the inhibition of protein isoprenylation index (IPI index). The 10 analogs showed a wide range of IPI indices. Two analogs, S3 and S9 had effects similar to, or stronger than, canventol. Three analogs, C44, C46 and C47, with lower IPI indices, inhibited tumor promotion on mouse skin slightly less than canventol itself did. This study shows that inhibition of protein isoprenylation in the cells, indicated by an increase in the IPI index, is a new biomarker for estimating inhibition of tumor promotion.

Topics: 3T3 Cells; Alkyl and Aryl Transferases; Animals; Anticarcinogenic Agents; Carcinogens; Cyclohexanols; Enzyme Inhibitors; Female; Lipid Metabolism; Mevalonic Acid; Mice; Mice, Inbred Strains; Okadaic Acid; Protein Prenylation; Skin Neoplasms; Sterols; Transferases; Ubiquinone

Topics: Alcohol Oxidoreductases; Aldehyde-Lyases; Amino Acid Oxidoreductases; Carcinoma, Basal Cell; Humans; Oxidoreductases; Skin; Skin Neoplasms; Ubiquinone

Topics: Alopecia Areata; Carcinoma, Basal Cell; Hair; Histocytochemistry; Humans; Melanoma; Mitochondria; Nevus; Skin; Skin Diseases; Skin Neoplasms; Ubiquinone