title: 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.affiliation: Department of Biochemistry, National University of Singapore, Singapore, Singapore.
authors.forename: Zheng Wei
authors.initials: ZW
authors.lastname: Lee
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Choon-Hong
authors.initials: CH
authors.lastname: Tan
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Philip Keith
authors.initials: PK
authors.lastname: Moore
authors.forename: Lih-Wen
authors.initials: LW
authors.lastname: Deng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D045325:HCT116 Cells; D018922:HL-60 Cells; D056945:Hep G2 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry*; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D006862:Hydrogen Sulfide