Abstract
Abstract Head and neck squamous cell carcinoma (HNSCC) accounts for 6% of all cancers in the United States, and unfortunately, the recurrence of secondary primary tumors, resistance and/or toxicity associated with conventional treatments decrease the overall 5-year survival rate in HNSCC patient. These limitations associated with therapies suggest that additional strategies are needed for the prevention/intervention of both primary as well as secondary primary tumors post HNSCC therapy. One such class of non-toxic agents is polyphenolic phytochemicals present in diet or those consumed as supplements. Grape seed extract (GSE) is one such dietary supplement that has received enormous attention in recent years due to its strong anti-cancer and chemopreventive potentials in several in vitro and in vivo studies. Here, for the first time, we investigated GSE efficacy employing human HNSCC Detroit 562 and FaDu cells as well as normal human epidermal keratinocytes (NHEK) both in vitro and in vivo. Our study showed that GSE selectively inhibited the growth and increased death in both HNSCC cell lines in a dose- and a time-dependent manner. GSE treatment (40 µg/ml for12-72 h) resulted in 18-80% (p<0.001) and 25-90% (p<0.001) decrease in live cell number, increased cell death by 8-49% and 9-40% (p<0.001) in Detroit 562 and FaDu cells compared to control, respectively. We found that GSE (20 and 40 µg/ml) resulted in increased accumulation of cells in G2/M-phase in dose- and time-dependent manner in both the cells lines. We also observed that GSE treatment for 24-72h resulted in significant increase in apoptotic cell death in both Detroit 562 and FaDu cells by activating DNA damage checkpoint cascade including ATM/ATR-Chk1/2-Cdc25C as well as caspases 8, 9 and 3. Consistent with this, GSE treatment also resulted in a strong DNA damage as indicated by increased phosphorylation of γ-H2AX and decreased the levels of DNA repair molecules Brca1 and Rad51 as well as the DNA repair foci, thereby; possibly sensitizing these cells towards GSE induced cell death. Furthermore, our study also showed that GSE caused accumulation of intra-cellular reactive oxygen species (ROS) was identified as a major mechanism of its effect for growth inhibition, DNA damage and apoptosis, which was remarkably reversed by thiol antioxidant N-acetylcysteine (NAC). GSE feeding to nude mice decreased Detroit 562 and FaDu xenograft tumor growth by 67% and 65% (p<0.001), respectively. In IHC analysis, xenografts from GSE-fed groups showed decreased proliferation but increased DNA damage and apoptosis. Together, these findings show that GSE targets both DNA damage and repair, and provide mechanistic insights for its efficacy selectively against HNSCC both in cell culture and mouse xenograft; supporting its translational potential against HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1598. doi:1538-7445.AM2012-1598
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