Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Shirsath, N; Rathos, M; Chaudhari, U; Sivaramakrishnan, H; Joshi, K.
Potentiation of anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the cyclin-dependent kinase inhibitor P276-00 in human non-small-cell lung cancer cell lines.
Lung Cancer. 2013; 82(2):214-221
Doi: 10.1016/j.lungcan.2013.08.010
Web of Science
PubMed
FullText
FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Shirsath Nitesh Pralhad
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- Abstract:
- P276-00 is a novel cyclin-dependent kinase (CDK) inhibitor is in Phase II clinical trials. Valproic acid (VPA), an antiepileptic agent has been associated with anticancer activity, through the inhibition of histone deacetylase I. Here we investigate the effect of the combination of VPA and P276-00, in non-small-cell lung cancer (NSCLC) cell lines. Cell growth inhibition was studied using the Propidium iodide (PI) assay. Cell cycle analysis and recovery were detected by flow cytometry. The expression levels of various proteins were detected by western blot. Inhibition of colony formation in H460 was checked in vitro. In vivo efficacy was studied in H460 xenograft model. The combination of P276-00 and VPA showed synergistic effect on p53+ and p53- NSCLC cell lines in antiproliferative assay at both constant and non-constant ratio with marked decrease in colony forming potential. Flow cytometric analysis confirmed a significant time dependent increase in apoptosis with 64% apoptotic population at 96 h compared to VPA (1%) and P276-00 (28%) alone (p < 0.0001). Incubation of the cells after treatment, in fresh medium without drugs, led to the recovery of cells treated with P276-00 alone but not the cells treated with the combination of both the drugs. The combination treatment up-regulated tumor suppressor proteins like p53, p21 and p27 along with down-regulation of proliferation and survival proteins viz. cyclin D1 and Bcl-2. This was also associated with the upregulation of the pro-apoptotic protein Bax and significant accumulation of hyperacetylated histones in the combination treatment. Interestingly, VPA in combination with P276-00 was much more effective as an antitumor agent than alone, in the H460 xenograft tumor model in SCID mice. This study indicates that the combination of HDAC inhibitor VPA with CDK inhibitor P276-00 is promising novel molecularly targeted therapeutic approach for NSCLC treatment. Copyright © 2013. Published by Elsevier Ireland Ltd.
- Find related publications in this database (using NLM MeSH Indexing)
- Acetylation -
- Animals -
- Antineoplastic Agents - pharmacology Antineoplastic Agents - toxicity
- Apoptosis - drug effects
- Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism
- Cell Cycle - drug effects
- Cell Cycle Proteins - metabolism
- Cell Line, Tumor -
- Cyclin-Dependent Kinases - antagonists & inhibitors Cyclin-Dependent Kinases - metabolism
- Flavones - pharmacology
- Histone Deacetylase Inhibitors - pharmacology Histone Deacetylase Inhibitors - toxicity
- Histones - metabolism
- Humans -
- Lung Neoplasms - drug therapy Lung Neoplasms - metabolism
- Mice -
- Protein Kinase Inhibitors - pharmacology
- Tumor Stem Cell Assay -
- Valproic Acid - pharmacology Valproic Acid - toxicity
- Xenograft Model Antitumor Assays -
- Find related publications in this database (Keywords)
- CDK inhibitor
- P276-00
- Valproic acid
- HDAC
- Combination studies
- Non-small-cell lung cancinoma