Non-small-cell lung cancer (NSCLC) represents approximately 80% of all types of lung cancer, and the dismal 5-year survival rate of about 14% has shown no improvement over the past three decades. Histone deacetylases (HDACs) regulate many biologic processes, including cell cycle progression and cell differentiation. Among HDACs, class I HDACs are frequently overexpressed in various human cancers and this overexpression correlates with drug resistance and poor prognosis. Thus, class I HDACs have been considered as potential therapeutic targets for the treatment of cancers. Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia plant, on NSCLC cells and the molecular mechanisms underlying these effects using in vitro and in vivo models. Treatment of NSCLC cells (A549, H1299, H460 and H226) with honokiol (20, 40 and 60 μM) inhibited histone deacetylase (HDAC) activity, reduced the levels of class I HDAC proteins and enhanced histone acetyltransferase activity in a dose-dependent manner. These effects of honokiol were associated with a significant reduction in the viability of NSCLC cells. Concomitant treatment of cells with a proteasome inhibitor, MG132, prevented honokiol-induced degradation of class I HDACs, suggesting that honokiol reduced the levels of HDACs in NSCLC cells through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of NSCLC cells. Treatment of A549 and H1299 cells with honokiol resulted in an increase in G1 phase arrest, and a decrease in the levels of cyclin D1, D2, and cyclin dependent kinases. Further, administration of honokiol by oral gavage (100 mg/kg body weight of mice) significantly inhibited the growth of s.c. A549 and H1299 tumor xenografts in athymic nude mice, which was associated with the induction of apoptotic cell death and marked inhibition of class I HDACs proteins and HDAC activity in the tumor xenograft tissues. Together, our study provides new insights and previously unrecognized role of class I HDACs in the chemotherapeutic effects of honokiol on lung cancer cells. These new insights into the epigenetic mechanism of action of honokiol may contribute to the chemoprevention or treatment of lung cancer and may have important implications for epigenetic therapy.

Key words: Apoptotic index, cell cycle, histone, histone deacetylase, histone acetyl transferase, honokiol, non-small cell lung cancer

Citation Format: Tripti Singh, Ram Prasad, Santosh K. Katiyar. Inhibition of class I histone deacetylases in non-small cell lung cancer cells by honokiol leads to suppression of cancer cell proliferation and induction of cell death in vitro and in vivo models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3672. doi:10.1158/1538-7445.AM2013-3672