Abstract
We studied the mechanism of ascorbate toxicity in malignant mesothelioma (MMe) cells.
Neutral red uptake showed that ascorbate, but not dehydroascorbate, was highly toxic in the MMe cell lines REN and MM98, and less toxic in immortalized (human mesothelial cells-htert) and primary mesothelial cells.
Ascorbate transport inhibitors phloretin, sodium azide, and ouabain did not reduce ascorbate toxicity.
Ascorbate promoted the formation of H(2)O(2) in the cell medium, and its toxicity was suppressed by extracellular catalase, but the concentration of endogenous catalase was higher in MMe cells than in normal cells.
The confocal imaging of cells loaded with the dihydrhodamine 123 reactive oxygen species probe showed that ascorbate caused a strong increase of rhodamine fluorescence in MMe cells, but not in mesothelial cells. MMe cells showed a higher production of superoxide and NADPH oxidase (NOX)4 expression than did mesothelial cells.
Two inhibitors of cellular superoxide sources (apocynin and rotenone) reduced ascorbate toxicity and the ascorbate-induced rise in rhodamine fluorescence. NOX4 small interfering RNA also reduced ascorbate toxicity in REN cells.
Taken together, the data indicate that ascorbate-induced extracellular H(2)O(2) production induces a strong oxidative stress in MMe cells because of their high rate of superoxide production.
This explains the selective toxicity of ascorbate in MMe cells, and suggests its possible use in the clinical treatment of malignant mesothelioma.
See also:
- Official Web Site: The Di Bella Method;
- The Di Bella Method (A Fixed Part - Vitamin C/Ascorbic Acid, 2–4 grams, twice a day orally);
- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);
- The Di Bella Method (A Variable Part - Chondroitin sulfate, up to 3-4 grams per day, orally);
- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;
- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);
- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);
- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);
- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);
- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);
- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);
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- Pleural Mesothelioma: clinical records on 11 patients treated with Di Bella's Method;
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