The slow-releasing hydrogen sulfide (H2S) donor, GYY4137, caused concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS) but did not affect survival of normal human lung fibroblasts (IMR90, WI-38) as determined by trypan blue exclusion. Sodium hydrosulfide (NaHS) was less potent and not active in all cell lines. A structural analogue of GYY4137 (ZYJ1122) lacking sulfur and thence not able to release H2S was inactive. Similar results were obtained using a clonogenic assay. Incubation of GYY4137 (400 µM) in culture medium led to the generation of low (<20 µM) concentrations of H2S sustained over 7 days. In contrast, incubation of NaHS (400 µM) in the same way led to much higher (up to 400 µM) concentrations of H2S which persisted for only 1 hour. Mechanistic studies revealed that GYY4137 (400 µM) incubated for 5 days with MCF-7 but not IMR90 cells caused the generation of cleaved PARP and cleaved caspase 9, indicative of a pro-apoptotic effect. GYY4137 (but not ZYJ1122) also caused partial G2/M arrest of these cells. Mice xenograft studies using HL-60 and MV4-11 cells showed that GYY4137 (100–300 mg/kg/day for 14 days) significantly reduced tumor growth. We conclude that GYY4137 exhibits anti-cancer activity by releasing H2S over a period of days. We also propose that a combination of apoptosis and cell cycle arrest contributes to this effect and that H2S donors should be investigated further as potential anti-cancer agents.

Abstract

The role of hydrogen sulfide (H2S) in inflammation is controversial, with both pro- and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H2S, which give a rapid bolus of H2S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H2S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H2S donor (GYY4137) on the release of pro- and antiinflammatory mediators in lipopolysaccharide (LPS)-treated murine RAW264.7 macrophages. For the first time, we show that GYY4137 significantly and concentration-dependently inhibits LPS-induced release of proinflammatory mediators such as IL-1β, IL-6, TNF-α, nitric oxide (•NO), and PGE2 but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-κB/ATF-2/HSP-27–dependent pathways. In contrast, NaHS elicited a biphasic effect on proinflammatory mediators and, at high concentrations, increased the synthesis of IL-1β, IL-6, NO, PGE2 and TNF-α. This study clearly shows that the effects of H2S on the inflammatory process are complex and dependent not only on H2S concentration but also on the rate of H2S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro- versus antiinflammatory role of H2S. Antioxid. Redox Signal. 12, 1147–1154.

Objective To examine the causal effects of doctor-patient relations and the severity of a medical outcome on medical patient perceptions and malpractice intentions in the event of an adverse medical outcome. Design Randomized between-subjects experimental design. Patients were given scenarios depicting interactions between an obstetric patient and her physician throughout the patient's pregnancy, labor, and delivery. Participants One hundred twenty-eight postpartum obstetric patients were approached for participation, of whom 104 completed the study. Main outcome measures Patients' perceptions of physician competence and intentions to file a malpractice claim. Results Positive physician communication behaviors increased patients' perceptions of physician competence and decreased malpractice claim intentions toward both the physician and the hospital. A more severe outcome increased only patients' intentions to sue the hospital. Conclusion These results provide empiric evidence for a direct, causal effect of the doctor-patient relationship on medical patients' treatment perceptions and malpractice claim intentions in the event of an adverse medical outcome.

Interviews with 400 consecutive patients attending a general practice sought their knowledge of the signs and symptoms of an acute heart attack, what action they would take for such an event, and their understanding of the predisposing factors contributing to heart disease. The survey revealed poor recognition of the relevant signs and symptoms of an acute heart attack and lack of knowledge of some of the main predisposing factors associated with heart disease.

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