Fig. 15.
The bell-shaped concentration-response of H2S in cancer. H2S in the low-to-medium concentration range serves signaling functions, stimulates cellular bioenergetics, exerts cytoprotective effects, while high concentrations of H2S are generally cytotoxic. High-CBS-expressor cancer cells upregulate their H2S generation so that they are near the top of the bell-shaped H2S concentration-response curve, so that they best benefit from the supporting actions of H2S. This is beneficial for the cancer cell, but detrimental to the tumor-bearing host. Arrow #1: Inhibition of CBS-mediated H2S production in cancer cells can “take away” the stimulatory effects of H2S on cellular signaling and bioenergetics and can suppress cancer cell proliferation; this intervention, on its own, is typically not directly cytotoxic. However, CBS inhibition can synergize with the effect of chemotherapeutic agents (Arrow #2). Addition of lower concentrations of H2S to cancer cells may, in some conditions, induce a further proliferative or cytoprotective effect, by moving the cells to the “top” of the H2S concentration-response curve (Arrow #3), but donation of H2S, at higher concentrations, moves the curve to the right, where the suppressive bioenergetic and cytotoxic effects of H2S prevail (Arrow #4).