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Modulatory effect of dexamethasone on temozolomide induced
apoptosis in human glioblastoma U87MG cells
Arabinda Das, Kunal D. Patel, Marc S. Weinberg, Sunil J.
Patel, Naren L. Banik, Swapan K. Ray
Medical University of South Carolina, Charleston,
SC. E-mail: raysk@musc.edu
Glioblastoma is the deadliest and most prevalent brain tumor.
Currently, there is no cure for glioblastona.
However, the general strategy for the treatment of glioblastoma involves
surgery, radiotherapy, and/or chemotherapy.
There are various adjuvant and chemotherapeutic drugs, which are often used in
combination with a hope of better outcome.
Dexamethasone (DXM) is a steroid commonly used for treatment of glioblastoma
patients for alleviation of pain and vasogenic edema prior to treatment with
chemotherapeutic drugs.
Temozolomide (TMZ), an alkylating chemotherapeutic drug, has recently been
introduced in clinical trials for treatment of glioblastoma.
This investigation was designed to determine the modulatory effect of DXM on TMZ
induced apoptosis in human glioblastoma U87MG cells.
Freshly grown cells were treated with different doses of DXM or TMZ for 6 h
followed by incubation in drug-free medium for 48 h.
Wright staining and ApopTag assay showed no apoptosis in U87MG cells treated
with 40 µM DXM but significant amounts of apoptosis in cells treated with 100
µM TMZ.
Apoptosis in TMZ treated U87MG was associated with an increase in intracellular
free [Ca2+], as determined by fura-2 assay.
Western blot analyses showed alterations in the levels of Bax (pro-apoptotic)
and Bcl-2 (anti-apoptotic) proteins with an increase in Bax/Bcl-2 ratio in TMZ
treated cells, indicating a commitment to apoptosis.
Western blot analyses also detected overexpression of calpain and caspase-3,
which cleaved 230 kD a-spectrin at specific sites for generation of 145 and 120
kD spectrin break down products (SBDPs), respectively.
However, 1-h pretreatment of U87MG cells with 40 µM DEX dramatically decreased
TMZ induced apoptosis, decreasing Bax/Bcl-2 ratio and SBDPs.
Thus, our results revealed that DXM was antagonistic to TMZ induced apoptosis in
human glioblastoma U87MG cells.
This study has yet to be substantiated in the xenografted and allografted animal
models of glioblastoma.
This investigation, however, strongly implies that treatment of glioblastoma
patients with DXM prior to chemotherapy with TMZ may result in an undesirable
clinical outcome.
Supported in part by five R01 grants from the National Cancer Institue (NCI) and
National Institue of Neurological Disorders ans Stroke (NINDS) of the National
Institutes of Health (NIH), and also a grant from the state of SC.
Copyright © 2004 American Association for Cancer Research.
All rights reserved.
Source: http://aacr04.agora.com/planner/displayabstract.asp?presentationid=4018
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