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

Lee ZW, Zhou J, Chen CS, Zhao Y, Tan CH, Li L, Moore PK, Deng LW - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, National University of Singapore, Singapore, Singapore.

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.

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Related in: MedlinePlus

Effect of GYY4137 on tumor growth in vivo.Changes in volume of established tumors in, (A) HL-60 xenograft mice (B) MV4–11 xenograft mice treated daily with either GYY4137 (100, 200 and 300 mg/kg, i.p.) or vehicle control. Treatment with GYY4137 significantly reduced the tumor volume in both animal models, in a dose-dependent manner. Results show changes of tumor volume in mean ± s.e. mean (n = 4–6, # P<0.05; * P<0.01).
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pone-0021077-g004: Effect of GYY4137 on tumor growth in vivo.Changes in volume of established tumors in, (A) HL-60 xenograft mice (B) MV4–11 xenograft mice treated daily with either GYY4137 (100, 200 and 300 mg/kg, i.p.) or vehicle control. Treatment with GYY4137 significantly reduced the tumor volume in both animal models, in a dose-dependent manner. Results show changes of tumor volume in mean ± s.e. mean (n = 4–6, # P<0.05; * P<0.01).

Mentions: Subcutaneous transplantation of either HL-60 or MV4–11 cells resulted in time-dependent tumor growth in the SCID mouse (Figure 4A, B). Tumor volume at the end of the experiment was 3024±220 mm3 and 1166±199 mm3 (n = 4–6) in animals receiving daily vehicle injection and administered HL-60 and MV4-11 cells respectively. Administration of GYY4137 on a daily basis resulted in a significant (P<0.05) dose related inhibition of tumor growth in both sets of animals. GYY4137 (at the highest dose used i.e. 300 mg/kg) administered daily for 14 days reduced tumor volume by 52.5±9.2% (n = 6) and 55.3±5.7% (n = 4) in HL-60 and MV4–11 injected animals. Although not measured objectively in these experiments, GYY4137 treatment did not affect animal weight or gross behavior.


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

Lee ZW, Zhou J, Chen CS, Zhao Y, Tan CH, Li L, Moore PK, Deng LW - PLoS ONE (2011)

Effect of GYY4137 on tumor growth in vivo.Changes in volume of established tumors in, (A) HL-60 xenograft mice (B) MV4–11 xenograft mice treated daily with either GYY4137 (100, 200 and 300 mg/kg, i.p.) or vehicle control. Treatment with GYY4137 significantly reduced the tumor volume in both animal models, in a dose-dependent manner. Results show changes of tumor volume in mean ± s.e. mean (n = 4–6, # P<0.05; * P<0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119065&req=5

pone-0021077-g004: Effect of GYY4137 on tumor growth in vivo.Changes in volume of established tumors in, (A) HL-60 xenograft mice (B) MV4–11 xenograft mice treated daily with either GYY4137 (100, 200 and 300 mg/kg, i.p.) or vehicle control. Treatment with GYY4137 significantly reduced the tumor volume in both animal models, in a dose-dependent manner. Results show changes of tumor volume in mean ± s.e. mean (n = 4–6, # P<0.05; * P<0.01).
Mentions: Subcutaneous transplantation of either HL-60 or MV4–11 cells resulted in time-dependent tumor growth in the SCID mouse (Figure 4A, B). Tumor volume at the end of the experiment was 3024±220 mm3 and 1166±199 mm3 (n = 4–6) in animals receiving daily vehicle injection and administered HL-60 and MV4-11 cells respectively. Administration of GYY4137 on a daily basis resulted in a significant (P<0.05) dose related inhibition of tumor growth in both sets of animals. GYY4137 (at the highest dose used i.e. 300 mg/kg) administered daily for 14 days reduced tumor volume by 52.5±9.2% (n = 6) and 55.3±5.7% (n = 4) in HL-60 and MV4–11 injected animals. Although not measured objectively in these experiments, GYY4137 treatment did not affect animal weight or gross behavior.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, National University of Singapore, Singapore, Singapore.

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.

Show MeSH
Related in: MedlinePlus