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Targeting procaspase-3 with WF-208, a novel PAC-1 derivative, causes selective cancer cell apoptosis.

Wang F, Liu Y, Wang L, Yang J, Zhao Y, Wang N, Cao Q, Gong P, Wu C - J. Cell. Mol. Med. (2015)

Bottom Line: Caspase-3 is a critical effector caspase in apoptosis cascade, and is often over-expressed in many cancer tissues.WF-208 also showed greater antitumour activity than PAC-1 in murine xenograft model.In conclusion, we have discovered WF-208 as a promising procaspase-3 activating compound, with higher activity and higher cell selectivity than PAC-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.

No MeSH data available.


Related in: MedlinePlus

WF-208 induced HL-60 and U-937 apoptosis through the activation of procaspase-3 to caspase-3. (A) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in HL-60 cells (upon) and U-937 (below) at different time and concentration. *P < 0.05 versus control group. (B) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in U-937 cells. The representative image of WF-208 (upon) and activation rate of WF-208 and PAC-1 (below) induced procaspase-3 cleavage in U-937 cells at different time and concentration. *P < 0.05 versus control group. (C) Phosphatidylserine exposure (measured by Annexin V/PI co-staining, describe as the percentage of Annexin V-positive PI-negative cell percentage) in HL-60 and U-937 after 24 h treatment with 2, 10, 50 μM WF-208. (D) The inhibition of 50 μM vancaspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK), caspase-8 inhibitor (Z-LETD-FMK), caspase-9 inhibitor (Z-LEHD-FMK) on early apopsotis induced by 10 μM WF-208 in HL-60 and U-937 cell lines treatment 24 hrs. *P < 0.05 versus control, #P < 0.05 versusWF-208 alone.
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fig04: WF-208 induced HL-60 and U-937 apoptosis through the activation of procaspase-3 to caspase-3. (A) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in HL-60 cells (upon) and U-937 (below) at different time and concentration. *P < 0.05 versus control group. (B) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in U-937 cells. The representative image of WF-208 (upon) and activation rate of WF-208 and PAC-1 (below) induced procaspase-3 cleavage in U-937 cells at different time and concentration. *P < 0.05 versus control group. (C) Phosphatidylserine exposure (measured by Annexin V/PI co-staining, describe as the percentage of Annexin V-positive PI-negative cell percentage) in HL-60 and U-937 after 24 h treatment with 2, 10, 50 μM WF-208. (D) The inhibition of 50 μM vancaspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK), caspase-8 inhibitor (Z-LETD-FMK), caspase-9 inhibitor (Z-LEHD-FMK) on early apopsotis induced by 10 μM WF-208 in HL-60 and U-937 cell lines treatment 24 hrs. *P < 0.05 versus control, #P < 0.05 versusWF-208 alone.

Mentions: Caspase-3 is one of the most crucial proteins of apoptosis, which exists as zymogen procaspase-3 before activation. After protein cleavage, procaspase-3 transform into its active form, caspase-3, followed by translocate from cytoplasm to nuclei 3. As shown in Figure4, immunofluoresence staining for cleaved caspase-3 was detected by high content analysis system. Nucleus was stained with Hoechst 33342. After treatment with 10 μM of WF-208 for 1 hr, cleaved caspase-3 was observed. After treatment for 24 hrs, procaspase-3 was cleaved in more than 60% cells (Fig.4A and B). At the same concentrations, the apoptosis per cent of WF-208 group was significant higher than which in PAC-1 group (Fig.4A and B). Chromatin condensation was also apparent in Hoechst-33342-stained HL-60 and U-937 treated with WF-208. These results indicate that WF-208 could activate procaspase-3 in time- and concentration-dependent manner in culture cells.


Targeting procaspase-3 with WF-208, a novel PAC-1 derivative, causes selective cancer cell apoptosis.

Wang F, Liu Y, Wang L, Yang J, Zhao Y, Wang N, Cao Q, Gong P, Wu C - J. Cell. Mol. Med. (2015)

WF-208 induced HL-60 and U-937 apoptosis through the activation of procaspase-3 to caspase-3. (A) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in HL-60 cells (upon) and U-937 (below) at different time and concentration. *P < 0.05 versus control group. (B) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in U-937 cells. The representative image of WF-208 (upon) and activation rate of WF-208 and PAC-1 (below) induced procaspase-3 cleavage in U-937 cells at different time and concentration. *P < 0.05 versus control group. (C) Phosphatidylserine exposure (measured by Annexin V/PI co-staining, describe as the percentage of Annexin V-positive PI-negative cell percentage) in HL-60 and U-937 after 24 h treatment with 2, 10, 50 μM WF-208. (D) The inhibition of 50 μM vancaspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK), caspase-8 inhibitor (Z-LETD-FMK), caspase-9 inhibitor (Z-LEHD-FMK) on early apopsotis induced by 10 μM WF-208 in HL-60 and U-937 cell lines treatment 24 hrs. *P < 0.05 versus control, #P < 0.05 versusWF-208 alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig04: WF-208 induced HL-60 and U-937 apoptosis through the activation of procaspase-3 to caspase-3. (A) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in HL-60 cells (upon) and U-937 (below) at different time and concentration. *P < 0.05 versus control group. (B) WF-208 and PAC-1 induced the cleavage of procaspase- 3 to caspase-3 in U-937 cells. The representative image of WF-208 (upon) and activation rate of WF-208 and PAC-1 (below) induced procaspase-3 cleavage in U-937 cells at different time and concentration. *P < 0.05 versus control group. (C) Phosphatidylserine exposure (measured by Annexin V/PI co-staining, describe as the percentage of Annexin V-positive PI-negative cell percentage) in HL-60 and U-937 after 24 h treatment with 2, 10, 50 μM WF-208. (D) The inhibition of 50 μM vancaspase inhibitor (Z-VAD-FMK), caspase-3 inhibitor (Z-DEVD-FMK), caspase-8 inhibitor (Z-LETD-FMK), caspase-9 inhibitor (Z-LEHD-FMK) on early apopsotis induced by 10 μM WF-208 in HL-60 and U-937 cell lines treatment 24 hrs. *P < 0.05 versus control, #P < 0.05 versusWF-208 alone.
Mentions: Caspase-3 is one of the most crucial proteins of apoptosis, which exists as zymogen procaspase-3 before activation. After protein cleavage, procaspase-3 transform into its active form, caspase-3, followed by translocate from cytoplasm to nuclei 3. As shown in Figure4, immunofluoresence staining for cleaved caspase-3 was detected by high content analysis system. Nucleus was stained with Hoechst 33342. After treatment with 10 μM of WF-208 for 1 hr, cleaved caspase-3 was observed. After treatment for 24 hrs, procaspase-3 was cleaved in more than 60% cells (Fig.4A and B). At the same concentrations, the apoptosis per cent of WF-208 group was significant higher than which in PAC-1 group (Fig.4A and B). Chromatin condensation was also apparent in Hoechst-33342-stained HL-60 and U-937 treated with WF-208. These results indicate that WF-208 could activate procaspase-3 in time- and concentration-dependent manner in culture cells.

Bottom Line: Caspase-3 is a critical effector caspase in apoptosis cascade, and is often over-expressed in many cancer tissues.WF-208 also showed greater antitumour activity than PAC-1 in murine xenograft model.In conclusion, we have discovered WF-208 as a promising procaspase-3 activating compound, with higher activity and higher cell selectivity than PAC-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.

No MeSH data available.


Related in: MedlinePlus