Survival of primary, but not of cancer cells after combined Plk1-HDAC inhibition

• Published in: Oncotarget 2015-09, Vol.6 (28), p.25801-25814
• Main Authors: Lange, Lisa, Hemmerich, Peter, Spänkuch, Birgit
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Benzylamines - pharmacology; Caspase 3 - pharmacology; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; G2 Phase Cell Cycle Checkpoints - drug effects; HeLa Cells; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Mice; NIH 3T3 Cells; Phosphorylation; Polo-Like Kinase 1; Poly(ADP-ribose) Polymerases - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyridines - pharmacology; Research Paper; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - enzymology; Retinal Pigment Epithelium - pathology; Retinoblastoma Protein - metabolism; Signal Transduction - drug effects; Telomerase - genetics; Telomerase - metabolism; Time Factors; Transfection; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - enzymology; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology; Vorinostat
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4445

In the current study we examined the combination of SAHA and SBE13 in cancer and non-cancer cells. HeLa cells displayed a synergistically reduced cell proliferation, which was much weaker in hTERT-RPE1 or NIH-3T3 cells. Cell cycle distribution differed in HeLa, hTERT-RPE1 and NIH-3T3 cells. SAHA-treated HeLa cells showed slightly increasing cell numbers in G2/M phase, but after combination with SBE13 strongly elevated cell numbers in G2/M and S phase, accompanied by decreasing G0/G1 percentages. hTERT-RPE1 and NIH-3T3 cells showed strongly enriched cell numbers in G0/G1 phase. Western blot and quantitative real time analyses revealed reduced Plk1 mRNA and protein in all cells. p21 protein was strongly induced in cancer, but not in non-cancer cells, corresponding to a different localization in immunofluorescence studies. Additionally, these revealed an abundantly present pRb protein in HeLa cells after any treatment but almost completely vanished pRb staining in treated hTERT-RPE1 cells. These differences could be approved in Western blots against Parp and Caspase 3, which were activated in HeLa, but not in hTERT-RPE1 cells. Thus, we observed for the first time a differential effect of cancer versus non-cancer cells after treatment with SAHA and SBE13, which might be due to the dual role of p21.