Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment

A high level of homocysteine (Hcy) is associated with oxidative/ER stress, apoptosis, and impairment of angiogenesis, whereas hydrogen sulfide (H(2)S) has been found to reverse this condition. Recent studies have shown that cancer cells need to produce a high level of endogenous H(2)S to maintain cell proliferation, growth, viability, and migration. However, any novel mechanism that targets this balance of Hcy and H(2)S production has yet to be discovered or exploited. Cells require homocysteine metabolism via the methionine cycle for nucleotide synthesis, methylation, and reductive metabolism, and this pathway supports the high proliferative rate of cancer cells. Although the methionine cycle favors cancer cells for their survival and growth, this metabolism produces a massive amount of toxic Hcy that somehow cancer cells handle very well. Recently, research showed specific pathways important for balancing the antioxidative defense through H(2)S production in cancer cells. This review discusses the relationship between Hcy metabolism and the antiapoptotic, antioxidative, anti-inflammatory, and angiogenic effects of H(2)S in different cancer types. It also summarizes the historical understanding of targeting antioxidative defense systems, angiogenesis, and other protective mechanisms of cancer cells and the role of H(2)S production in the genesis, progression, and metastasis of cancer. This review defines a nexus of diet and precision medicine in targeting the delicate antioxidative system of cancer and explores possible future therapeutics that could exploit the Hcy and H(2)S balance.