The activation of protein kinase C (PKC) contributes to tumor survival and proliferation provoking the development of inhibitory agents that may function as cancer therapeutics. Pseudomonas exotoxin-based immunotoxins are antibody-based recombinant proteins that employ an ADP-ribosylation domain for the enzymatic inhibition of protein synthesis of target cancer cells. Combining PKC inhibitors with immunotoxins was undertaken to explore possible synergy. Enzastaurin but not two other PKC inhibitors (Sortastaurin and G06976) combined with immunotoxins directed to surface mesothelin or the transferrin receptor to produce synergistic or additive cell death via apoptosis. Enhancement of killing was noted with enzastaurin concentrations of 5 uM or greater. Mechanistic insights of the combined immunotoxin-enzastaurin killing centered on the rapid complete loss of the prosurvival Bcl2 protein, Mcl-1, and the activation of caspase 3/7. Moreover, efficient cell killing was associated with loss of Akt and the BH3-only protein Bad. Enzastaurin-mediated enhanced cell killing was specific to Pseudomonas exotoxin-based immunotoxins as there was no enhancement with other agents that inhibit protein synthesis such as cycloheximide and diphtheria toxin. Immunotoxin-enzastaurin combinations could be useful for the treatment of human cancers that express mesothelin and are not efficiently killed by SS1P alone.

Citation Format: Abid R. Mattoo, Ira Pastan, David Fitzgerald. The cytotoxic activity of the anti-mesothelin immunotoxin SS1P is enhanced by the PKC inhibitor enzastaurin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5490. doi:10.1158/1538-7445.AM2013-5490

©2013 American Association for Cancer Research
2013