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Tamoxifen Induces Cytotoxic Autophagy in Glioblastoma.

Al's Comment:

 I had a relative do great for over 5 years with high dose tamoxifen for her gbm.  It was relatively popular before Temodar came into use. Studies showed that it helped a small % of patients, but when it helped, it helped a lot. And it had minimal side effects.  This article  might explain why it helps some patients and not others. More research needs to be done.


Posted on: 08/18/2016

J Neuropathol Exp Neurol. 2016 Aug 11. pii: nlw071. [Epub ahead of print]
Tamoxifen Induces Cytotoxic Autophagy in Glioblastoma.
Graham CD1, Kaza N1, Klocke BJ1, Gillespie GY1, Shevde LA1, Carroll SL1, Roth KA2.
 
Author information:
1From the Department of Pathology (CDG, NK, BJK, LAS, SLC, KAR); and Department of Neurosurgery, University of Alabama at Birmingham (GYG), Birmingham, Alabama.
2From the Department of Pathology (CDG, NK, BJK, LAS, SLC, KAR); and Department of Neurosurgery, University of Alabama at Birmingham (GYG), Birmingham, Alabama kar2208@cumc.columbia.edu.
 
Abstract
 
Glioblastomas (GBMs) are the most common and aggressive primary human malignant brain tumors. 4-Hydroxy tamoxifen (OHT) is an active metabolite of the tamoxifen (TMX) prodrug and a well-established estrogen receptor (ER) and estrogen-related receptor antagonist. A recent study from our laboratory demonstrated that OHT induced ER-independent malignant peripheral nerve sheath tumor (MPNST) cell death by autophagic degradation of the prosurvival protein Kirsten rat sarcoma viral oncogene homolog. Because both MPNST and GBM are glial in cell origin, we hypothesized that OHT could mediate similar effects in GBM. OHT induced a concentration-dependent reduction in cell viability that was largely independent of caspase activation in a human GBM cell line and 2 patient-derived xenolines. Further, OHT induced both cytotoxic autophagy and a concentration-dependent decrease in epidermal growth factor receptor (EGFR) protein levels. A GBM cell line expressing EGFR variant III (EGFRvIII) was relatively resistant to OHT-induced death and EGFRvIII was refractory to OHT-induced degradation. Thus, OHT induces GBM cell death through a caspase-independent, autophagy-related mechanism and should be considered as a potential therapeutic agent in patients with GBM whose tumors express wild-type EGFR.
 
© 2016 American Association of Neuropathologists, Inc. All rights reserved.

 


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