PAC-1 is a procaspase-activating compound; activates procaspase-3 to produce caspase-3 (EC50 = 0.22 μM). PAC-1 enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Signaling through the neuropeptide GPCR PAC(1) induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.
|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|
|Preparation method||Determination of IC50 values in various cell lines.
Various concentrations of etoposide or PAC-1 were added to cells and incubated for 24 h and 72 h for etoposide and PAC-1, respectively. Cell death was quantified by the addition of MTS/PMS CellTiter 96 Cell Proliferation Assay reagent (Promega). The plates were incubated at 37 1C for approximately 1 h (until the colored product formed), and the absorbance was measured at 490 nm.
|Incubation time||24 h and 72 h|
|Animal models||nude mice bearing NCI-H226 xenograft model|
|Formulation||mixture of 24:1 vegetable oil/DMSO|
|Dosages||50 and 100 mg/kg once a day for 21 d|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥48 mg/mL|
Signaling through the neuropeptide GPCR PAC1 induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor.
Emery et al. FASEB J. 2012 Aug;26(8):3199-211. PMID: 22532442.
Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3.
Peterson et al. J Med Chem. 2009 Sep 24;52(18):5721-31. PMID: 19708658.
Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy.
Putt KS, et al. Nat Chem Biol. 2006 Oct;2(10):543-50. PMID: 16936720.
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