J. Cancer Mol. 3:
147-153, 2007
[Research Paper]
Anti-Tumor Effect of Doxycycline on Glioblastoma Cells
Andrea
Wang-Gillam, Eric Siegel, Debra A. Mayes, Laura F. Hutchins, and Yi-Hong
Zhou
Department of Internal Medicine, Washington
University in St.Louis, St. Louis, MO, USA [A. Wang-Gillam];
Arkansas Cancer Research Center, University of Arkansas for Medical
Sciences, Little Rock, AR, USA [E. Siegel; L. F. Hutchins]; Department
of Neuroscience, University of Cincinnati, Cincinnati, OH, USA [D. A.
Mayes]; Department of Neurological Surgery, University of California,
Irvine, CA, USA [Y.-H. Zhou]
Abstract:
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
zymography 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.
(Keywords:
doxycycline; matrix metalloproteinase 2; cell invasion; glioma cell
lines)
_________________________________________________________________________________________________
Received:
9/10/07; Revised: 10/26/07; Accepted: 10/28/07.
1Correspondence:
Dr.
Yi-Hong Zhou, Department of Neurological Surgery, University of
California, Irvine, No. 101, The City
Drive, Building 56, Suit 400, Zot
5397,
Orange, CA
92868, USA. Phone: 1-949-8245767.
Fax:
1-714-4568284.
E-mail:
yihongz@uci.edu
2Abbreviations:
GBM, glioblastoma multiforme; MMP2, matrix metalloproteinase 2;
QRT-PCR, quantitative reverse transcriptase-polymerase chain reaction;
MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.
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