Anti-invasion and anti-tumor growth effect of doxycycline treatment for human oral squamous-cell carcinoma - In vitro and in vivo studies

Regional lymph node and distant organ metastasis of oral squamous-cell carcinoma (OSCC) has been associated with increased production of matrix metalloproteases (MMPs), and scientific data showed that doxycycline (Dox) could down-regulate the expression of MMPs. The objective of this study was to evaluate the effect of Dox on the expression of MMPs in vitro using the SCC-15 cell line and in vivo SCC-15 xenografted nude mice. SCC-15 cells maintained under distinct culture conditions expressed high levels of pro-MMP-2 and pro-MMP-9; however, as determined by zymography and Western blot analysis, Dox significantly reduced the production of pro-MMP-2 and pro-MMP-9 after 24 h of treatment in a dose-dependent manner (2.5-40 mu g/ml). Dox (10 mu g/ml) decreased the expression of MMP-9 mRNA but did not alter the level of MMP-2 mRNA after 24 h of treatment. In addition, this drug significantly inhibited the invasive and migration activities of SCC-15 cells in vitro (>75% inhibition at 10 mu g/ml). On the other hand, daily administration of Dox (3 mg/mice) restrained tumor growth in SCC-15 xenografted nude mice, with an inhibition rate of 85.6%. Compared with the control group (treated with normal saline), MMP-9 mRNA levels in the fresh tumor tissue decreased upon Dox treatment (P < 0.01) while MMP-2 mRNA levels were unchanged. In conclusion, reduced expression of MMP-9 at the transcriptional level and MMP- 2 at the post-transcriptional level caused by Dox was found to be associated with decreased invasion of oral SCC in vitro. Moreover, Dox exerted a significant suppressive effect on tumor growth in an in vivo nude mice model. Taken together, these results, to our knowledge, may first imply that Doxycycline has an adjuvant therapeutic effect on OSCC that is associated with inhibition of MMPs expression. (C) 2009 Elsevier Ltd. All rights reserved.