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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 decreases IAPs by promoting its degradation by the proteasome. (A) The effects of WF-208 on Bcl-2 family proteins at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (B) The effects of WF-208 on XIAP and Survivin at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (C) The effects of WF-208 on XIAP and survivin mRNA at different concentration measured by real-time PCR. (D) The effects of WF-208 combined with Ac-DEVD-FMK, Ac-VAD-FMK and MG132 on XIAP and survivin in 10 μM at 24 hrs. (E) The effects of WF-208 at different concentration after treatment 24 hrs of treatment on XIAP and survivin in normal HL-60 cells and procaspase-3 silenced HL-60 cells. (F) The effects of 5, 10 μM ZnSO4 co-treatment with WF-208 on XIAP and survivin in HL-60 after 24 hrs. (G) The cytotoxicity of WF-208 co-treatment with 10 μM ZnSO4 against HL-60 after 24 hrs.
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fig06: WF-208 decreases IAPs by promoting its degradation by the proteasome. (A) The effects of WF-208 on Bcl-2 family proteins at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (B) The effects of WF-208 on XIAP and Survivin at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (C) The effects of WF-208 on XIAP and survivin mRNA at different concentration measured by real-time PCR. (D) The effects of WF-208 combined with Ac-DEVD-FMK, Ac-VAD-FMK and MG132 on XIAP and survivin in 10 μM at 24 hrs. (E) The effects of WF-208 at different concentration after treatment 24 hrs of treatment on XIAP and survivin in normal HL-60 cells and procaspase-3 silenced HL-60 cells. (F) The effects of 5, 10 μM ZnSO4 co-treatment with WF-208 on XIAP and survivin in HL-60 after 24 hrs. (G) The cytotoxicity of WF-208 co-treatment with 10 μM ZnSO4 against HL-60 after 24 hrs.

Mentions: To investigate the effects of WF-208 on other pro-apoptotic and anti-apoptotic proteins, the Bcl-2 family proteins (Fig.6A) and XIAP family proteins (Fig.6B) were detected. After treatment of various concentrations of WF-208 for 24 hrs, the expression of Bcl-2 family members, Bcl-2, Bcl-xl, Bax and BID, was not changed (Fig.6A). However, the expression of IAP family XIAP and survivin were significantly down-regulated by WF-208 in a concentration-depended manner (Fig.6B). These data suggest that IAP family members, but not Bcl-2 family members, are likely to play an important role in WF-208-induced apoptosis of malignant tumour 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 decreases IAPs by promoting its degradation by the proteasome. (A) The effects of WF-208 on Bcl-2 family proteins at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (B) The effects of WF-208 on XIAP and Survivin at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (C) The effects of WF-208 on XIAP and survivin mRNA at different concentration measured by real-time PCR. (D) The effects of WF-208 combined with Ac-DEVD-FMK, Ac-VAD-FMK and MG132 on XIAP and survivin in 10 μM at 24 hrs. (E) The effects of WF-208 at different concentration after treatment 24 hrs of treatment on XIAP and survivin in normal HL-60 cells and procaspase-3 silenced HL-60 cells. (F) The effects of 5, 10 μM ZnSO4 co-treatment with WF-208 on XIAP and survivin in HL-60 after 24 hrs. (G) The cytotoxicity of WF-208 co-treatment with 10 μM ZnSO4 against HL-60 after 24 hrs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549042&req=5

fig06: WF-208 decreases IAPs by promoting its degradation by the proteasome. (A) The effects of WF-208 on Bcl-2 family proteins at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (B) The effects of WF-208 on XIAP and Survivin at different concentration after 24 hrs were measured by Western blot analyses in HL-60 and U-937 cell lines. (C) The effects of WF-208 on XIAP and survivin mRNA at different concentration measured by real-time PCR. (D) The effects of WF-208 combined with Ac-DEVD-FMK, Ac-VAD-FMK and MG132 on XIAP and survivin in 10 μM at 24 hrs. (E) The effects of WF-208 at different concentration after treatment 24 hrs of treatment on XIAP and survivin in normal HL-60 cells and procaspase-3 silenced HL-60 cells. (F) The effects of 5, 10 μM ZnSO4 co-treatment with WF-208 on XIAP and survivin in HL-60 after 24 hrs. (G) The cytotoxicity of WF-208 co-treatment with 10 μM ZnSO4 against HL-60 after 24 hrs.
Mentions: To investigate the effects of WF-208 on other pro-apoptotic and anti-apoptotic proteins, the Bcl-2 family proteins (Fig.6A) and XIAP family proteins (Fig.6B) were detected. After treatment of various concentrations of WF-208 for 24 hrs, the expression of Bcl-2 family members, Bcl-2, Bcl-xl, Bax and BID, was not changed (Fig.6A). However, the expression of IAP family XIAP and survivin were significantly down-regulated by WF-208 in a concentration-depended manner (Fig.6B). These data suggest that IAP family members, but not Bcl-2 family members, are likely to play an important role in WF-208-induced apoptosis of malignant tumour 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