Fig. 11.

Various roles of H₂S as a cytoprotective factor in cancer cells. H₂S can lead to the upregulation of various antioxidant systems. H₂S can stimulate Nrf2/ARE pathway through: sulfhydration of Keap1 (at Cys151), that in turn, undergoes a conformational change which leads to the dissociation of Nrf2 from the Keap1-Cul3-RBX1 E3 ligase complex. Subsequently, the free Nrf2 translocates into the nucleus to induce a global change in gene expression, which includes the upregulation of a host of antioxidant genes and enzyme systems. H₂S can stimulate PI3K/Akt, ERK1/2 and mTOR pathways, already discussed in Fig. 10. H₂S can stimulate NF-kB pathway through: sulfhydration of NF-kB at Cys38. H₂S can stimulate HSP90 pathway. The activation of these pathways confers general cytoprotection and cancer cell resistance to chemotherapeutic agents induced cytotoxicity. However, in the context of chemotherapeutic agents, additional, more specific mechanisms may also be involved in the protection provided by H₂S. H₂S can stimulate STAT3/Akt/Bcl-2 pathway through Akt activation. H₂S can also promote the upregulation of P-glycoprotein (P-gp) and thymidylate synthetase (TYMS).