Homocysteine, Thioretinaco Ozonide, and Oxidative Phosphorylation in Cancer and Aging: A Proposed Clinical Trial Protocol

  • Kilmer S. McCullyEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1866)


The objective of the proposed clinical interventional trial is to demonstrate the efficacy of a novel therapeutic strategy in subjects with cancer and hyperhomocysteinemia. Following discovery of abnormal homocysteine thiolactone metabolism in cultured malignant cells, thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone, and thioretinaco, the complex formed from cobalamin and thioretinamide, were demonstrated to have antineoplastic, anticarcinogenic, and anti-atherogenic properties in animal models. Retinol, ascorbate, and homocysteine thiolactone are necessary for biosynthesis of thioretinamide and thioretinaco by cystathionine synthase and for formation of thioretinaco ozonide from thioretinamide, cobalamin, and ozone. Thioretinaco ozonide is required for prevention of abnormal oxidative metabolism, aerobic glycolysis, suppressed immunity, and hyperhomocysteinemia in cancer.

The pancreatic enzyme therapy of cancer promotes catabolism of proteins, nucleic acids, and glycosaminoglycans with excess homocysteinylated amino groups resulting from abnormal accumulation of homocysteine thiolactone in malignant cells. Dietary deficiencies of pyridoxal, folate, cobalamin, and nitriloside contribute to hyperhomocysteinemia in cancer, and in protein energy malnutrition. A deficiency of dietary sulfur amino acids downregulates cystathionine synthase, causing hyperhomocysteinemia.

The organic sulfur compound diallyl trisulfide increases hydrogen sulfide production from homocysteine in animal models, inhibits Stat3 signaling in cancer stem cells, and produces apoptosis of malignant cells. The furanonaphthoquinone compound napabucasin inhibits Stat3 signaling and causes mitochondrial dysfunction, decreased oxidative phosphorylation, and apoptosis of malignant cells. The protocol of the proposed clinical trial in subjects with myelodysplasia consists of thioretinamide and cobalamin as precursors of thioretinaco ozonide, combined with pancreatic enzyme extracts, diallyl trisulfide, napabucasin, nutritional modification to minimize processed foods, vitamin supplements, essential amino acids, and beneficial dietary fats and proteins.

Key words

Adenosyl methionine Apoptosis Cystathionine synthase Diallyl trisulfide Homocysteine thiolactone Hyperhomocysteinemia Myelodysplasia Napabucasin Oxidative phosphorylation Pancreatic enzymes Thioretinamide Thioretinaco ozonide Clinical trial 


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Authors and Affiliations

  1. 1.Department of PathologyHarvard Medical SchoolBostonUSA
  2. 2.Pathology and Laboratory Medicine ServiceVA Boston Healthcare SystemBostonUSA

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