Enzastaurin inhibits PKCβ, PKCα, PKCγ and PKCε with IC50's of 0.006, 0.039, 0.083 and 0.110 µM, respectively. Enzastaurin apparently inhibits tumor growth via multiple mechanisms: suppression of tumor cell proliferation, induction of tumor cell apoptosis and inhibition of tumor-induced angiogenesis.
|Cell lines||PC-3 prostate cancer, HCT116 colon cancer, and U87MG glioblastoma cell lines|
|Preparation method||Proliferation assays. Proliferation was assessed for all cell lines over a 6-day time course in media supplemented with 1% FBS (7 days total). Briefly, 1,000 cells were plated per well in a 96-well plate and changed to fresh media (1% FBS) with or without enzastaurin on days 1 and 4. On day 7, the media were removed and 100 μL propidium iodide (PI) solution (10 μg/mL in D-PBS) were added to each well. An initial reading for PI staining (excitation at 500 nmol/L, absorbance at 615 nmol/L) was done using the WallacVictor plate reader following a 30-minute incubation to determine the nonviable cell fraction. The plate was then frozen at −80 °C for 2 hours, thawed, and reread. The proliferative index was scored by subtracting the prefreeze data (nonviable cells) from the postfreeze data (all cells).|
|Incubation time||6 days|
|Animal models||Athymic nude mice bearing HCT116 colon cancer xenografts|
|Formulation||10% acacia (Fisher Scientific, Fair Lawn, NJ) in water|
|Dosages||twice daily at 75 mg/kg|
|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.
A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer.
Grønberg et al. Lung Cancer. 2012 Aug 20. PMID: 22917813.
A Multicenter Phase II Study of Single-Agent Enzastaurin in Previously Treated Waldenstrom Macroglobulinemia.
Ghobrial et al. Clin Cancer Res. 2012 Aug 28. PMID: 22879385.
A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer.
Clément-Duchêne et al. Lung Cancer. 2012 Jul 16. PMID: 22809813.
Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics.
Nwankwo et al. Invest New Drugs. 2012 Jul 6. PMID: 22766773.
Combination of low doses of Enzastaurin and Lenalidomide has synergistic activity in B-non-Hodgkin lymphoma cell lines.
Cosenza et al. Ann Hematol. 2012 Oct;91(10):1613-22. PMID: 22623160.
Enzastaurin has anti-tumour effects in lung cancers with overexpressed JAK pathway molecules.
Shimokawa et al. Br J Cancer. 2012 Feb 28;106(5):867-75. PMID: 22333600.
A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054).
Rampling et al. Neuro Oncol. 2012 Mar;14(3):344-50. PMID: 22291006.
|Related PKC Products|
Chelerythrine is potent, cell-permeable inhibitor of protein kinase C (IC50 = 660 nM); competitive with respect to the phosphate acceptor and non-competitive with respect to ATP.
1-Naphthyl PP1(1-NA-PP 1) is a selective inhibitor of src family kinases v-Src and c-Fyn as well as the tyrosine kinase c-Abl (IC50 values are 1.0, 0.6, 0.6, 18 and 22 μM for v-Src, c-Fyn, c-Abl, CDK2 and CAMK II respectively).
|Zoledronic acid monohydrate
Zoledronic acid monohydrate(CGP 42446; ZOL 446) is an activator of protein kinase C with apoptotic effects on multiple myeloma cell lines. It inhibited proliferation of human foetal osteoblastic cell line (hFOB) with an IC50 of 40 uM.
Ingenol Mebutate is a substance found in the sap of the plant Euphorbia peplus and an inducer of cell death.
|Phorbol 12-myristate 13-acetate
Phorbol 12-myristate 13-acetate (PMA) is a PKC-activating phorbol ester, increases the intracellular Ca2+ concentration ([Ca2+]i) in a dose-dependent manner, with an EC50 of 11.7 nM.
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