title: Combinatorial inhibition of Plk1 and PKCβ in cancer cells with different p53 status.
abstract: PKCβ and Plk1 are fascinating targets in cancer therapy. Therefore, we combined Enzastaurin targeting PKCβ and SBE13 targeting Plk1 to test synergistic effects in cells with different p53 status. We analyzed cell proliferation and apoptosis induction, and did Western blot and FACScan analyses to examine the combined PKCβ and Plk1 inhibition. p53-wild-type cells are more resistant to the combinatorial treatment than p53-deficient cells, which displayed a synergistic reduction of cell proliferation after the combination. HeLa, MCF-7 and HCT116(p53wt) and HCT116(p53-/-) cells differed in their cell cycle distribution after combinatorial treatment in dependence on a functional p53-dependent G1/S checkpoint (p53-deficient cells showed an enrichment in S and G2/M, p53-wild-type cells in G0/G1 phase). hTERT-RPE1 cells did not show the synergistic effects of cancer cells. Thus, we demonstrate for the first time that Plk1 inhibition using SBE13 enhances the effects of Enzastaurin in cancer cells. HCT116(p53wt) and HCT116(p53-/-) cells confirmed the p53-dependence of different effects after Plk1 and PKCβ inhibition observed in HeLa and MCF-7 cells. Obviously, p53 protects cells from the cytotoxicity of Enzastaurin in combination with SBE13. For that reason this combination can be useful to treat p53-deficient cancers, without displaying toxicity to normal cells, which all have functional p53.
authors.affiliation: Friedrich-Schiller-University, CMB, Institute for Biochemistry, Hans-Knöll-Straße 2, 07745 Jena, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lange
authors.forename: Sarah
authors.initials: S
authors.lastname: Keppner-Witter
authors.forename: Juline
authors.initials: J
authors.lastname: Grigat
authors.forename: Birgit
authors.initials: B
authors.lastname: Spänkuch
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines / Q000494:pharmacology*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000097869:Polo-Like Kinase 1
chemical_list: D001596:Benzylamines; D018797:Cell Cycle Proteins; D007211:Indoles; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C549033:SBE13 compound; C495901:TP53 protein, human; C504878:enzastaurin