Anti-Tumor Effect of Doxycycline on Glioblastoma Cells

AIM: Glioblastoma multiforme (GBM) is the most common primary brain tumor in humans, and it is highly invasive. Doxycycline, first identified as an antimicrobial agent, is a nonspecific inhibitor of matrix metalloproteinases (MMPs). Our objective was to investigate the anti-MMP effect of doxycycline at therapeutically acceptable levels on glioma cells in vitro. METHODS: The MTT assay was used to determine the anti-proliferative effects of doxycycline. MMP2 activity and expression were determined by gelatinase zymo-graphy and real-time quantitative RT-PCR, respectively. Cell invasion was assessed by Matrigel invasion assay. RESULTS: Doxycycline exerted mild anti-proliferative effects on all three glioma cell lines (U251HF, U87 and LN229). In U251HF cells, doxycycline decreased extracellular MMP2 activity and reduced cell invasiveness. Moreover, MMP2 mRNA levels were not altered, suggesting that doxycycline regulates MMP2 activity post-translationally. Alternatively, doxycycline increased the expression and extracellular activity of MMP2 in U87 cells. This may reflect the cellular stress-response related to the cytotoxic effects experienced by U87 cells in response to doxycycline exposure. CONCLUSION: Doxycycline in therapeutic concentrations decreases MMP2 activity and cell invasion in the most aggressive cell line tested, suggesting its potential as a therapeutic MMP inhibitor. The cytotoxic effects of doxycycline, however, can enhance MMP2 expression, and this deserves further exploration