The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo.

Abstract

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.

• Authors: Zheng Wei Lee, Jianbiao Zhou, Chien-Shing Chen, Yujun Zhao, Choon-Hong Tan, Ling Li, Philip Keith Moore, Lih-Wen Deng
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e21077 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21701688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• GYY 4137
• Morpholines
• Organothiophosphorus Compounds
• Hydrogen Sulfide

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• HCT116 Cells
• HL-60 Cells
• Hep G2 Cells
• Humans
• Hydrogen Sulfide (chemistry)
• Mice
• Mice, SCID
• Morpholines (chemistry, pharmacology, therapeutic use)
• Organothiophosphorus Compounds (chemistry, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays