Anti-Cancer Drugs. 19(9):841-848, October 2008. [Link]

Faoro, Leonardo a; Loganathan, Sivakumar a; Westerhoff, Maria b; Modi, Rahul a; Husain, Aliya N. b; Tretiakova, Maria b; Seiwert, Tanguy a; Kindler, Hedy L. a; Vokes, Everett E. a; Salgia, Ravi a


Malignant pleural mesothelioma (MPM) is a disease with few therapeutic options. Protein kinase C beta (PKC[beta]) is involved in important cellular functions. Enzastaurin (LY317615.HCl) is a novel inhibitor of PKC in clinical development. MPM cell lines (7) and patient tumor tissues (24) were evaluated for expression of PKC[beta] by immunoblotting and immunohistochemistry, respectively. In-vitro cell growth assays were performed with enzastaurin with or without cisplatin. Cell migration was evaluated with the wound healing assay. Downstream signaling (survival and focal adhesion pathways) was studied by immunoblotting for related molecules in the presence of phorbol ester with or without enzastaurin. Expression for PKC[beta]1 was seen in all cases, with a mean integrated optical density of 152.5 (standard deviation=95.47, n=24), whereas PKC[beta]2 expression was less intense, with a mean integrated optical density of 11.45 (standard deviation=16.27, n=21). There was a trend toward lower overall survival among patients expressing above-median PKC[beta]1 (P=0.064), but not PKC[beta]2. Robust expression of PKC[beta]1 and low expression of PKC[beta]2 were observed in MPM cell lines. Treatment of MPM cell lines with enzastaurin revealed an IC50 of 5 [mu]mol/l, and strong synergism was observed when combined with cisplatin. Wound healing assay revealed that treatment of H2461 cells with enzastaurin reduced migration by 59.2%. Enzastaurin treatment led to disruption of F-actin architecture. Downstream signaling showed reduced phosphorylation of AKT, FAK (focal adhesion kinase), p130Cas, S6 ribosomal protein, and paxillin. PKC[beta]1 was expressed in the majority of MPM samples. Enzastaurin has preclinical activity against MPM, and exhibited synergism with cisplatin. PKC[beta] inhibition in MPM might be able to reduce the invasiveness of MPM by affecting cytoskeletal function.