Enzastaurin, as the inhibitor of PKC, may be a novel PNC medical therapy

Pancreatic cancer is the fourth most common cause of cancer death both in the United States. Regarding the pathology, pancreatic cancer mainly includes exocrine pancreas cancers, pancreatic cystic neoplasms and endocrine pancreatic cancers. Pancreatic neuroendocrine cancers (PNC) account for less than 3% of pancreatic tumors and the main treatments are surgery, hormone therapy, chemotherapy and so on at this stage. However, It is still needed to search for effective treatments for PNC, and understand the molecular pathways regulating neuroendocrine tumor cell proliferation.

The serine–threonine protein kinase C(PKC) plays important regulatory roles in a multitude of cellular processes including proliferation, differentiation, apoptosis, and secretion, and is reported to contribute to the progression of several tumors. Enzastaurin, a PKCβ-selective inhibitor, suppresses not only PKC signaling but also the PI3 kinase (PI3K)/Akt pathway and thus regulates tumor cell survival and proliferation. The two signaling pathways mentioned above are found to be the most dysregulated in PNC, indicating a possible effects of PKC inhibitors on this disease.

In the paper by Daniela Mole et al., Enzastaurin significantly reduced primary PNC cell viability, inhibit BON1 cell proliferation and induced cell apoptosis. Further mechanism was studied and the data showed that Enzastaurin reduced phosphorylation of glycogen synthetase kinase 3b (GSK3b) and of Akt, downstream targets of PKC pathway. Moreover, an antisecretory effect of Enzastaurin was observed, since Enzastaurin was capable of reducing both basal and IGF1 stimulated CgA and insulin secretion[1].

Taken together, Enzastaurin, as the inhibitor of PKC, can inhibit cell growth and induce cell apoptosis, suggesting that PKC may represent a new pharmacological target for PNC medical therapy.
[1]. Endocrine-Related Cancer (2011) 18 439–450

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S1055 Enzastaurin (LY317615) Enzastaurin (LY317615) is a potent PKCβ selective inhibitor with IC50 of 6 nM in cell-free assays, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε. Phase 3. (21) (4)

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