Cancer phase 1 enzyme inhibition

NO has a cytostatic effect by inhibiting ATP synthesis [99] via Kreb s cycle (aconitase inhibition, [100]), glycolysis (GADPH inhibition) and mitochondrial respiration (NAD ubiquinone oxydoreductase and succinate ubiquinone oxydoreductase inhibitions, [101]). Another pathway is the ornithine decarboxylase inhibition. This enzyme is implicated in polyamine production necessary to cell proliferation and its activity is inhibited by NO in human colon cancer cells HT-29 and Caco-2 [102]. Furthermore NO directly inactivates ribonucleotide reductase [103] of TA3 cancer cells (murine breast cancer cells) [104]. This enzyme controlling DNA synthesis catalyses desoxyribonucleotides synthesis, and its inhibition blocks cells in S phase. This inhibition is rapid and reversible in K562 and TA3 cells [105]. 

Conversely, to the (5)-enantiomer, it does not inhibit COX enzymes, but it is an apoptosis inductor. It is also in phase III evaluation for treatment of Alzheimer dementia vide infra) Celebrex, another NS AID drug, is also being evaluated for the treatment of several cancers. 

Topotecan and irinotecan both act by inhibiting topoisomerase I (topo I) enzymes, thereby inhibiting DNA replication. They are cell cycle-specific agents with most activity for cells in the S phase. Topotecan is used for treatment of refractory metastatic ovarian carcinoma and small cell lung cancer. It also may be useful in the treatment of head and neck cancer. Irinotecan is indicated for the treatment of metastatic carcinoma of the colon or rectum. 

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