Abstract
Purpose : To demonstrate the effect of histone deacetylase-inhibitor, vorinostat, on antitumour activity of grape seed proanthocyanidins (GSPs) in non-small cell lung cancer (NSCLC) cells. Methods : Expression of thymidine phosphorlase (TP) and thymidylate synthase (TS) was measured by real-time PCR and western blotting. TP knockdown was performed using specific small interfering RNA. Antitumour activity of combination of vorinostat and GSPs was assessed according to Chou and Talay method and by evaluating apoptosis. Results : Vorinostat treatment led to a significant increase in TP expression but decrease in TS expression in NSCLC cells. In H157 cells, increase in the concentration of vorinostat from 0.34 to 0.4 μM increased TP expression 3- to 6-fold. In H1299 cells, there was 7-fold reduction of TS transcript and 30-fold increase of TP transcript at 48 h. Vorinostat, when used in combination with GSPs, resulted in a synergistic anti-proliferative effect and increased apoptotic cell death. However, cells with TP knockdown did not exhibit vorinostat- and GSPs-mediated anti-proliferative effect and apoptotic cell death. Conclusion : The combination of vorinostat and GSPs can be an effective and innovative antitumour therapy for the treatment of NSCLC. Keywords : Histone deacetylase-inhibitor, Synergism, Apoptosis, Antitumor
Highlights
Grape seed proanthocyanidins (GSP), mixture of polyphenols and flavanols exhibit anticancer activity with least toxicity [1,2,3]
The synergistic effect was observed on treatment with equipotent doses of vorinostat and GSPs for 48 h at 50 % (CI50) or 75 % (CI75) of cell lethality (Table 2)
There was a dose reduction in IC50 values (DRI50) to 6-fold for both vorinostat and GSPs in combination compared with the concentrations of the two drugs alone
Summary
Grape seed proanthocyanidins (GSP), mixture of polyphenols and flavanols exhibit anticancer activity with least toxicity [1,2,3]. Vorinostat (suberoylanilide hydroxamic acid), the most promising HDAC-I exhibited promising preclinical and clinical antitumour activity. It is the first HDAC-I approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease during or following two systemic therapies [7]. We provided evidence that by down regulating TS and up regulating TP mRNA and protein expression, vorinostat demonstrated synergistic antitumour activity in combination with GSPs. Vorinostat, GSPs, tubacin and niltubacin were purchased from Sigma-Aldrich, USA. The vorinostat-induced up regulation of TP enhanced TP transcript in A549 cells that was evident after 12 h with a 27-fold induction at 48 h. Sigma Stat software (Systat Software Inc., San Jose, California, USA) was used for all statistical evaluations
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