PAC-1

Item no.	S2738-10
Manufacturer	Selleckchem
CASRN	315183-21-2
Amount	10 mg
Quantity options	10 mg 1 g 10 g 10 mM/1 mL 25 mg 250 mg 50 mg 5 g
Category	Oncology Cardiovascular Research Ischemia & Reperfusion Injury Inhibitors & Compound Libraries Small Molecules By Organ Lung Cancer Colorectal Cancer Testicular & Prostate Cancer
Type	Inhibitors
Specific against	other
Smiles	C=CCC1=C(C(=CC=C1)C=NNC(=O)CN2CCN(CC2)CC3=CC=CC=C3)O
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	Procaspase-3,Caspase
Similar products	PAC-1
Available
Storage Conditions	2 years -80 in solvent
Molecular Weight	392, 49
Administration	Pellet implantation subcutaneously or oral gavage
Animal Models	Ovariectomized female athymic BALB/c (nude, nu/nu) mice injected subcutaneously with ACHN cells, male athymic BALB/c nude mice injected subcutaneously with NCI-H226 cells, and male athymic BALB/câ€“/â€“ mice injected intravenously with NCI-H226 cells
Cell lines	U-937, HL-60, CRL-1872, ACHN, NCI-H226, Hs888Lu, Hs578Bst, MCF-10A, SK-MEL-5, BT-20, MDA-MB-231, UACC-62, SK-N-SH, B16-F10 , Hs 578t, and PC-12
Concentrations	Dissolved in DMSO, final concentrations ca.100 uM
Dosages	ca.100 mg/kg
Formulation	Mixed with cholesterol and pelleted into a 3-mm-diameter 20-mg (total weight) pellet, or dissolved in a mixture of 24:1 vegetable oil/DMSO
IC50	0.22 uM [1], 0.22 uM [1], 0.22 uM [1], 0.22 uM [1], 0.22 uM [1], 0.22 uM [1]
In vitro	PAC-1 activates procaspase-7 in a less efficient manner with EC50 of 4.5 uM. Elevated caspase 3 level in cancer cell lines allows PAC-1 to selectively induce apoptosis in a manner proportional to procaspase-3 concentration with IC50 of 0.35 uM for NCI-H226 cells to ca.3.5 uM for UACC-62 cells. PAC-1 induces apoptosis in the primary cancerous cells with IC50 values of 3 nM to 1.41 uM, more potently than in the adjacent noncancerous cells with IC50 of 5.02 uM to 9.98 uM, which is also directly related to the distinct procaspase-3 concentration. [1] PAC-1 activates procaspase-3 by chelating zinc ions, thus relieving the zinc-mediated inhibition and allowing procaspase-3 to auto-activate itself to caspase-3. [2] PAC-1 is capable to induce cell death in Bax/Bak double-knockout cells and Bcl-2 and Bcl-xL-overexpressing cells with the same efficacy as its wild-type counterpart in a delayed manner. PAC-1 induces cytochrome c release in a caspase-3 independent manner, which subsequently triggers downstream caspase-3 activation and cell death. PAC-1 can not induce cell death and caspase-3 activation in Apaf-1 knockout cells, suggesting that apoptosome formation is essential for caspase-3 activation by PAC-1-mediated cell death. [3]
In vivo	Administration of PAC-1 at 5 mg with low and steady releasing significantly inhibits the growth of ACHN renal cancer xenograft in mice. Oral administration of PAC-1 (50 or 100 mg/kg) significantly retards tumor growth of NCI-H226 lung cancer xenograft in a dose-dependent manner, and markedly prevents the cancer cells from infiltrating the lung tissue. The in vivo anti-tumor effect of PAC-1 is ascribed to procaspase-3 activation and subsequently apoptosis induction consistent with the activity in vitro. [1]
Incubation Time	72 hours
Kinase Assay	In vitro procaspase-3 activation, Procaspase-3 is expressed and purified in Escherichia coli. Various concentrations of PAC-1 are added to 90 uL of a 50 ng/mL of procaspase-3 in caspase assay buffer in a 96-well plate, The plate is incubated for 12 hours at 37 C. A 10 uL volume of a 2 mM solution of caspase-3 peptidic substrate acetyl Asp-Glu-Val-Asp-p-nitroanilide (Ac-DEVD-pNa) in caspase assay buffer is then added to each well. The plate is read every 2 minutes at 405 nm for 2 hours in a Spectra Max Plus 384 well plate reader. The slope of the linear portion for each well is determined, and the relative increase in activation from untreated control wells is calculated.
Method	Cells are exposed to various concentrations of PAC-1 for 72 hours. Cell death is quantified by the addition of MTS/PMS CellTiter 96 Cell Proliferation Assay reagent. The plates are incubated at 37 C for approximately 1 hour (until the colored product formed), and the absorbance is measured at 490 nm.
Solubility (25C)	DMSO 78 mg/mL, Water <1 mg/mL, Ethanol 16 mg/mL
Information	PAC-1 is a potent procaspase-3 activator with EC50 of 0.22 μM and the first small molecule known to directly activate procaspase-3 to caspase-3.
Chemical Name	(E)-N'-(3-allyl-2-hydroxybenzylidene)-2-(4-benzylpiperazin-1-yl)acetohydrazide
Features	PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3

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