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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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GYY4137 but not NaHS significantly affected cancer cell survivability.(A) The effect of treatment (5 days) of a range of cancer and non-cancer cells with NaHS, GYY4137 and ZYJ1122 (400 µM or 800 µM) as determined by trypan blue staining. Results show percentage of cell viability to non-treatment (NT) following incubation in the absence of drug treatment and are mean ± s.e. mean, n = 3, (#P<0.05; *P<0.01). (B) Concentration-response curves showing the effect of GYY4137 treatment for 5 days on survival of MCF-7, HL-60 and MV4-11 cells. Results show mean ± s.e. mean, n = 3. (C) Representative photographs showing clonogenic survival assays of MCF-7 cells following exposure (5 days, 200–600 µM) to either NaHS (top row), GYY4137 (middle row) and ZYJ1122 (bottom row). NT =  non-treatment.
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pone-0021077-g002: GYY4137 but not NaHS significantly affected cancer cell survivability.(A) The effect of treatment (5 days) of a range of cancer and non-cancer cells with NaHS, GYY4137 and ZYJ1122 (400 µM or 800 µM) as determined by trypan blue staining. Results show percentage of cell viability to non-treatment (NT) following incubation in the absence of drug treatment and are mean ± s.e. mean, n = 3, (#P<0.05; *P<0.01). (B) Concentration-response curves showing the effect of GYY4137 treatment for 5 days on survival of MCF-7, HL-60 and MV4-11 cells. Results show mean ± s.e. mean, n = 3. (C) Representative photographs showing clonogenic survival assays of MCF-7 cells following exposure (5 days, 200–600 µM) to either NaHS (top row), GYY4137 (middle row) and ZYJ1122 (bottom row). NT =  non-treatment.

Mentions: To determine the effect of two different concentrations (400 µM and 800 µM) of GYY4137, NaHS and ZYJ1122 on a wider panel of human cancer cell lines, cell survival of a further four cancer cell lines of different origins i.e. cervical carcinoma (HeLa), colorectal carcinoma (HCT-116), hepatocellular carcinoma (Hep G2) and osteosarcoma (U2OS) cells was determined in comparison with two normal human diploid fibroblasts (WI-38 and IMR90) (Figure 2A). Over a 5-day culture period, NaHS (400 µM) failed to influence the survival of any of the seven cancer lines tested. In contrast, the effect of GYY4137 on cell survival was much more profound with 30–70% (P<0.01) death in all cancer cell lines at the same concentration. A higher concentration of NaHS (800 µM) resulted in a further, albeit small, reduction in HCT-116, Hep G2 and MCF-7 cell survival (approximately 15–30%) although again no significant difference in cell survival was apparent in HeLa, HL-60, U2OS and MV4-11 cells. In contrast, GYY4137 at the same concentration, markedly reduced survival by approximately 75–95% in all cancer cell lines. The absolute degree of cell death caused by GYY4137 varied between cancer cell lines with greatest effect in HepG2, HL-60, MV4–11, MCF-7 and U2OS cells and least effect in HCT-116 and HeLa cells. For this reason, subsequent experiments were conducted using one or more of HL-60, MCF-7 and MV4-11 cancer cells. Importantly, neither NaHS nor GYY4137 significantly changed the survival of human non-cancer WI-38 and IMR90 fibroblasts. The sulfur-lacking control compound, ZYJ1122, was without significant effect on the survival of any cell line, suggesting that the observed effects of GYY4137 on cancer cells are likely due to H2S release. The concentration response relationship for GYY4137 (100–1000 µM) to reduce cell survival was also examined in MCF-7, HL-60 and MV4-11 cells. The IC50 values for this compound were 337.1±15.4, 389.3±16.8 and 341.8±21.2 µM (all n = 3) respectively (Figure 2B).


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)

GYY4137 but not NaHS significantly affected cancer cell survivability.(A) The effect of treatment (5 days) of a range of cancer and non-cancer cells with NaHS, GYY4137 and ZYJ1122 (400 µM or 800 µM) as determined by trypan blue staining. Results show percentage of cell viability to non-treatment (NT) following incubation in the absence of drug treatment and are mean ± s.e. mean, n = 3, (#P<0.05; *P<0.01). (B) Concentration-response curves showing the effect of GYY4137 treatment for 5 days on survival of MCF-7, HL-60 and MV4-11 cells. Results show mean ± s.e. mean, n = 3. (C) Representative photographs showing clonogenic survival assays of MCF-7 cells following exposure (5 days, 200–600 µM) to either NaHS (top row), GYY4137 (middle row) and ZYJ1122 (bottom row). NT =  non-treatment.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3119065&req=5

pone-0021077-g002: GYY4137 but not NaHS significantly affected cancer cell survivability.(A) The effect of treatment (5 days) of a range of cancer and non-cancer cells with NaHS, GYY4137 and ZYJ1122 (400 µM or 800 µM) as determined by trypan blue staining. Results show percentage of cell viability to non-treatment (NT) following incubation in the absence of drug treatment and are mean ± s.e. mean, n = 3, (#P<0.05; *P<0.01). (B) Concentration-response curves showing the effect of GYY4137 treatment for 5 days on survival of MCF-7, HL-60 and MV4-11 cells. Results show mean ± s.e. mean, n = 3. (C) Representative photographs showing clonogenic survival assays of MCF-7 cells following exposure (5 days, 200–600 µM) to either NaHS (top row), GYY4137 (middle row) and ZYJ1122 (bottom row). NT =  non-treatment.
Mentions: To determine the effect of two different concentrations (400 µM and 800 µM) of GYY4137, NaHS and ZYJ1122 on a wider panel of human cancer cell lines, cell survival of a further four cancer cell lines of different origins i.e. cervical carcinoma (HeLa), colorectal carcinoma (HCT-116), hepatocellular carcinoma (Hep G2) and osteosarcoma (U2OS) cells was determined in comparison with two normal human diploid fibroblasts (WI-38 and IMR90) (Figure 2A). Over a 5-day culture period, NaHS (400 µM) failed to influence the survival of any of the seven cancer lines tested. In contrast, the effect of GYY4137 on cell survival was much more profound with 30–70% (P<0.01) death in all cancer cell lines at the same concentration. A higher concentration of NaHS (800 µM) resulted in a further, albeit small, reduction in HCT-116, Hep G2 and MCF-7 cell survival (approximately 15–30%) although again no significant difference in cell survival was apparent in HeLa, HL-60, U2OS and MV4-11 cells. In contrast, GYY4137 at the same concentration, markedly reduced survival by approximately 75–95% in all cancer cell lines. The absolute degree of cell death caused by GYY4137 varied between cancer cell lines with greatest effect in HepG2, HL-60, MV4–11, MCF-7 and U2OS cells and least effect in HCT-116 and HeLa cells. For this reason, subsequent experiments were conducted using one or more of HL-60, MCF-7 and MV4-11 cancer cells. Importantly, neither NaHS nor GYY4137 significantly changed the survival of human non-cancer WI-38 and IMR90 fibroblasts. The sulfur-lacking control compound, ZYJ1122, was without significant effect on the survival of any cell line, suggesting that the observed effects of GYY4137 on cancer cells are likely due to H2S release. The concentration response relationship for GYY4137 (100–1000 µM) to reduce cell survival was also examined in MCF-7, HL-60 and MV4-11 cells. The IC50 values for this compound were 337.1±15.4, 389.3±16.8 and 341.8±21.2 µM (all n = 3) respectively (Figure 2B).

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