Abstract
Activated protein kinase C (PKC) contributes to tumor survival and proliferation, provoking the development of inhibitory agents as potential cancer therapeutics. Immunotoxins are antibody-based recombinant proteins that employ antibody fragments for cancer targeting and bacterial toxins as the cytotoxic agent. Pseudomonas exotoxin-based immunotoxins act via the ADP-ribosylation of EF2 leading to the enzymatic inhibition of protein synthesis. Combining PKC inhibitors with the immunotoxin SS1P, targeted to surface mesothelin, was undertaken to explore possible therapeutic strategies. Enzastaurin but not two other PKC inhibitors combined with SS1P to produce synergistic cell death via apoptosis. Mechanistic insights of the synergistic killing centered on the complete loss of the prosurvival Bcl2 protein, Mcl-1, the loss of AKT and the activation of caspase 3/7. Synergy was most evident when cells exhibited resistance to the immunotoxin alone. Further, because PKC inhibition by itself was not sufficient to enhance SS1P action, enzastaurin must target other kinases that are involved in the immunotoxin pathway.
Highlights
Protein Kinase C (PKC) enzymes contribute to growth, survival and angiogenesis, all features that are frequently up-regulated in cancer [1]
Survey of PKC Inhibitors Because combination therapies are frequently more effective in cancer treatment than single agents, we evaluated three PKC inhibitors in combination with SS1P, an immunotoxin targeted to surface mesothelin
Enzastaurin, sotrastaurin and Go6976 at 5 and 10 uM were incubated with KB cells either alone or in combination with SS1P
Summary
Protein Kinase C (PKC) enzymes contribute to growth, survival and angiogenesis, all features that are frequently up-regulated in cancer [1]. In mammals there are eight homologous isoforms including four ‘conventional’ and four ‘novel’ enzymes. These serine-threonine kinases are configured with N-terminal regulatory domains and a C-terminal enzymatic domain. When targeting PKCs, inhibition of specific isoforms is complicated by the close similarity of C-terminal domains. Low molecular weight inhibitors that target a specific enzymatic domain are still likely to exhibit a range of inhibitory actions against most family members. This leads to an empirical approach whereby inhibitors are tested for effectiveness based on biochemical or phenotypic outcomes. We survey three known PKC inhibitors, enzastaurin [3], Go6976 [4] and sotrastaurin [5] and investigate their ability to enhance the killing of an immunotoxin directed to the cell surface antigen, mesothelin
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
