ubiquinone and Melanoma

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

The present study showed the development of nanocapsules containing the association of the coenzyme Q10 and vitamin E acetate and the evaluation of their effect on in vitro cells culture of malignant glioma and melanoma. In order to investigate if nanocapsules are able to protect coenzyme Q10 from degradation under UVC radiation, a photostability study was carried out. For this, three concentrations of vitamin E acetate were evaluated (1%, 2%, or 3%). Nanocapsules presented suitable physicochemical characteristics and were able to protect coenzyme Q10 from photodegradation. In addition, this protection was influenced by higher vitamin E acetate concentrations, attributing to this oil an important role on coenzyme Q10 photostabilization. Regarding to in vitro citotoxicity assay, nanocapsules containing coenzyme Q10 and 2% vitamin E significantly reduced glioma and melanoma cell viability in 61% and 66%, respectively. In this sense, these formulations represent interesting platforms for the delivery of coenzyme Q10 and vitamin E acetate, presenting effect on the reduction of malignant cells viability.

Topics: Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Cell Survival; Drug Stability; Glioma; Humans; Melanoma; Nanocapsules; Photolysis; Polymers; Ubiquinone; Vitamin E; Vitamins

Topics: Animals; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; Melanoma; Mice; Mice, Nude; Mitochondria; Proto-Oncogene Proteins B-raf; Ubiquinone; Xenograft Model Antitumor Assays

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

Deprivation of tyrosine (Tyr) and phenylalanine (Phe) inhibits growth and induces programmed cell death (apoptosis) of human A375 melanoma cells. Herein, we found that activation of caspases and release of mitochondrial cytochrome c are required for this process. Culturing A375 cells in Tyr/Phe-free medium, containing 10% dialyzed fetal bovine serum, results in activation of caspase-3-like activity. This is accompanied by decreased cell viability and increased apoptosis. Tyr/Phe deprivation also stimulates proteolytic cleavage of the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP). Western blot analysis showed that caspases 3, 7, 8, and 9 are activated by deprivation of Tyr/Phe. Tyr/Phe deprivation decreases mitochondrial membrane potential, induces cleavage of Bid, increases translocation of Bax from the cytosol to mitochondria, and results in release of cytochrome c from the mitochondria to the cytosol. Apoptosis due to Tyr/Phe deprivation is almost completely inhibited by the broad-spectrum cell-permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z.VAD.fmk). This inhibitor suppresses the cleavage of Bid, the release of cytochrome c from the mitochondria to the cytosol, and the cleavage of PARP. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, does not suppress the activation of caspase 8 but suppresses release of cytochrome c, activation of caspase 9, and induction of apoptosis. These results indicate that activation of caspases, cleavage of Bid, and mitochondrial release of cytochrome c are required for apoptosis induced by Tyr/Phe deprivation.

Topics: Amino Acid Chloromethyl Ketones; Amino Acids, Aromatic; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Blotting, Western; Carrier Proteins; Caspase Inhibitors; Caspases; Cysteine Proteinase Inhibitors; Cytochrome c Group; Fas Ligand Protein; fas Receptor; Humans; Ligands; Melanoma; Membrane Glycoproteins; Mitochondria; Models, Biological; Phenylalanine; Time Factors; Tumor Cells, Cultured; Tyrosine; 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

Effect of the additional treatment with coenzyme Q10 on immunorestoration with Mycobacterium bovis BCG in tumor-bearing mice was investigated. Cell-mediated cytotoxicity in tumor-bearing mice against alloantigenic tumor cells was determined by 51Cr release assay using spleen cells of C57BL/6N mice which had been inoculated subcutaneously with syngeneic melanoma-B16 and immunized intraperitoneally with alloantigenic mastocytoma P815-X2 cells. The cell-mediated cytotoxicity against mastocytoma P815-X2 cells was gradually depressed with the growth of melanoma-B16. The depressed, cell-mediated cytotoxicity in tumor-bearing mice recovered slightly by the treatment with BCG. The recovery effect of BCG on the depressed, cell-mediated cytotoxicity was significantly enhanced by the additional treatment with coenzyme Q10. Coenzyme Q10 did not have an apparent effect on the depressed, cell-mediated cytotoxicity in tumor-bearing mice. These results show that coenzyme Q10 enhances the immunorestoration with BCG in tumor-bearing mice.

Topics: Animals; BCG Vaccine; Drug Synergism; Female; Immunity, Cellular; Mast-Cell Sarcoma; Melanoma; Mice; Mycobacterium bovis; Neoplasm Transplantation; Neoplasms, Experimental; Ubiquinone

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

Topics: Adolescent; Adult; Aged; Brain Neoplasms; Bronchial Neoplasms; Esophageal Neoplasms; Female; Humans; Leukemia, Myeloid; Liver; Lung; Male; Melanoma; Middle Aged; Muscles; Pancreas; Pancreatic Neoplasms; Rectal Neoplasms; Ubiquinone; Uterine Neoplasms

Topics: Autoradiography; Female; Humans; Leg; Melanoma; Middle Aged; Neoplasms; Radiation Protection; Radioisotopes; Radiotherapy Dosage; Tritium; Ubiquinone; Vitamin K