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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

PAC-1 and WF-208 activated procaspase-3 in vitro. (A) Structures of PAC-1 and WF-208. (B) The PAC-1 and WF-208 activated rh-procaspase-3 in series of concentration 0.08–100 μM. (C) PAC-1 and WF-208 activated rh-procaspase-3 in zinc free vehicle and 5 μM ZnSO4 added vehicle. (D) The cleavage of procaspase-3 induced by WF-208 in zinc-free and 5 μM ZnSO4 buffer (PC3: procaspase-3, C3: caspase-3).
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fig02: PAC-1 and WF-208 activated procaspase-3 in vitro. (A) Structures of PAC-1 and WF-208. (B) The PAC-1 and WF-208 activated rh-procaspase-3 in series of concentration 0.08–100 μM. (C) PAC-1 and WF-208 activated rh-procaspase-3 in zinc free vehicle and 5 μM ZnSO4 added vehicle. (D) The cleavage of procaspase-3 induced by WF-208 in zinc-free and 5 μM ZnSO4 buffer (PC3: procaspase-3, C3: caspase-3).

Mentions: As shown in Figure2, the concentration-dependent activity of both WF-208- and PAC-1-induced procaspase-3 activation followed typical concentration-response curve in vitro. WF-208 significantly activated procaspase-3 (EC50 = 0.56 μM), which was more efficacious than PAC-1 (EC50 = 6.02 μM) (Fig.2B). Moreover, since previous studies have indicated that PAC-1 activates procaspase-3 through the inhibition of zinc chelation 14,23. In this study, the role of zinc in WF-208-induced procaspase-3 activation was also investigated. As shown in Figure2C, procaspase-3 in buffer without Zn2+ had high auto-activation. WF-208 activated procaspase-3 in the buffer containing 5 μM ZnSO4 rather than in the buffer without Zn2+. The Western blot results also revealed that zinc inhibits procaspase-3 auto-activation, and that WF-208 is able to revert this inhibition in a concentration-dependent manner.


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)

PAC-1 and WF-208 activated procaspase-3 in vitro. (A) Structures of PAC-1 and WF-208. (B) The PAC-1 and WF-208 activated rh-procaspase-3 in series of concentration 0.08–100 μM. (C) PAC-1 and WF-208 activated rh-procaspase-3 in zinc free vehicle and 5 μM ZnSO4 added vehicle. (D) The cleavage of procaspase-3 induced by WF-208 in zinc-free and 5 μM ZnSO4 buffer (PC3: procaspase-3, C3: caspase-3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: PAC-1 and WF-208 activated procaspase-3 in vitro. (A) Structures of PAC-1 and WF-208. (B) The PAC-1 and WF-208 activated rh-procaspase-3 in series of concentration 0.08–100 μM. (C) PAC-1 and WF-208 activated rh-procaspase-3 in zinc free vehicle and 5 μM ZnSO4 added vehicle. (D) The cleavage of procaspase-3 induced by WF-208 in zinc-free and 5 μM ZnSO4 buffer (PC3: procaspase-3, C3: caspase-3).
Mentions: As shown in Figure2, the concentration-dependent activity of both WF-208- and PAC-1-induced procaspase-3 activation followed typical concentration-response curve in vitro. WF-208 significantly activated procaspase-3 (EC50 = 0.56 μM), which was more efficacious than PAC-1 (EC50 = 6.02 μM) (Fig.2B). Moreover, since previous studies have indicated that PAC-1 activates procaspase-3 through the inhibition of zinc chelation 14,23. In this study, the role of zinc in WF-208-induced procaspase-3 activation was also investigated. As shown in Figure2C, procaspase-3 in buffer without Zn2+ had high auto-activation. WF-208 activated procaspase-3 in the buffer containing 5 μM ZnSO4 rather than in the buffer without Zn2+. The Western blot results also revealed that zinc inhibits procaspase-3 auto-activation, and that WF-208 is able to revert this inhibition in a concentration-dependent manner.

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