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Role of autophagy in temozolomide-induced cytotoxicity for
malignant glioma cells
Takao Kanzawa, Hideaki Ito, Yasuko Kondo, Seiji Kondo
The University of Texas M. D. Anderson Cancer
Center, Houston, TX. E-mail: seikondo@mdanderson.org
Autophagy is originally named as a process of protein recycling.
It begins with
sequestering cytoplasmic organelles in a membrane vacuole called autophagosome.
Autophagosomes then fuse with lysosomes, where the materials inside are degraded
and recycled.
To date, however, little is known about the role of autophagy in
cancer therapy.
In this study, we present that temozolomide (TMZ), a new
alkylating agent, inhibited the viability of
malignant glioma cells in a dose-dependent manner and induced G2/M arrest.
At a
clinically achievable dose (100 μM), TMZ induced autophagy, but not
apoptosis in malignant glioma cells.
After the treatment with TMZ,
microtubule-associated protein light chain 3 (LC3), a mammalian homologue
of Apg8p/Aut7p essential for amino acid starvation-induced autophagy in yeast,
was recruited on autophagosome membranes.
When autophagy was prevented at an
early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase
inhibitor, not only the characteristic pattern of LC3 localization, but also the
anti-tumor effect of TMZ was suppressed.
On the other hand, bafilomycin A1, a
specific inhibitor of vacuolar type H+-ATPase, that prevents
autophagy at a late stage by inhibiting fusion between autophagosomes and
lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through
activation of caspase-3 with mitochondrial and lysosomal membrane
permeabilization, while LC3 localization pattern stayed the same.
These results
indicate that TMZ induces autophagy in malignant glioma cells.
Application of an
autophagy inhibitor that works after the association of LC3 with autophagosome
membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ
for malignant gliomas.
Copyright © 2004 American Association for Cancer Research. All rights
reserved.
Source: http://aacr04.agora.com/planner/displayabstract.asp?presentationid=283
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