Approximately 80% of renal cell carcinomas are of the clear cell subtype ccRCC, and common characteristics of this cancer include inactivation of the Von Hippel-Lindau tumor suppressor, leading to dysregulation of HIF-1 and 2α transcription factors and ultimately a pseudohypoxic tumor signature. Altered metabolism and upregulation of angiogenic factors result, and while therapies addressing individual such shifts are employed, an approach that targets the fundamental basis of the dysregulated survival and proliferation of ccRCC cells would increase effectivity while reducing systemic side effects.

HypOxystation users Sonke et al. in Canada examined the involvement of hydrogen sulfide H2S in angiogenesis, cytoprotection and metabolism in VHL-deficient ccRCC, where endogenous H2S accumulates as mitochondrial oxidation ceases under hypoxia and pseudo-hypoxia (“Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential; Nitric Oxide. 2015 Sep 15;49:26-39 “). The Sonke lab used the H85 HypOxystation by Don Whitley Scientific to examine the influence of hypoxia (1%) and normoxia on the expression of the H2S-producing enzymes CBS, CSE and MPS; cell viability under treatment with hydroxylamine HA, a CBS/CSE inhibitor, was also compared at normoxia and at hypoxia in the HypOxystation. The closed hypoxic environment created in the HypOxystation provides stable parameters favoring in vivo physiology of cancer cells. Using an avian chorioallantoic membrane xenograft system, they examined the inhibitory effects of H2S on neovascularization.

Inactivation of Von Hippel-Lindau protein initiates a pseudo-hypoxic phenotype in ccRCC and promotes cancer progression, aided by hydrogen sulfide which enhances tumor progression by fostering cellular bioenergetics, stimulating migratory and invasive signaling pathways, and enhancing tumor angiogenesis. Sonke et al. found that, in contrast to some other cancers (colon and ovarial), expression of H2S-producing enzymes is not increased in ccRCC. Inhibition of H2S production increases oxidative stress in the cell, decreases cellular energy production and reduces vascularization, in addition to disrupting the signaling pathways that maintain cancer stem cells through induction of stem cell factors OCT4 and NANOG. The Sonke lab concluded that inhibitors of endogenous H2S production may represent a promising therapeutical approach for the targeted treatment of VHL-deficient, pseudo-hypoxic renal carcinoma.