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Tamoxifen modulation of etoposide cytotoxicity involves
inhibition of protein kinase C activity and insulin-like growth factor II
expression in brain tumor cells
Cheppail Ramachandran, Ziad Khatib,
Athena Pefkarou, John Fort, Hugo B. Fonseca, Steven J. Melnick and Enrique
Escalon
Research Institute
(C.R.., H.B.F.), Division of Hematology/Oncology (Z.K., A.P., J.F., E.E.) and
Department of Pathology (S.J.M), Miami Children’s Hospital, Miami, FL, USA. cheppail.ramachandran@mch.com.
Tamoxifen, a non-steroidal anti-estrogen widely used against breast cancer, is
also useful for treatment of other malignancies, due to its sensitizing effect
on other chemotherapeutic agents and radiation.
We have investigated the
advantages of combining tamoxifen with one of the commonly used cancer
chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines.
While
tamoxifen (10 microM) increased etoposide cytotoxicity 8.3-fold in the human
glioma cell line (HTB-14), it increased etoposide cytotoxicity 47.5- and 40-fold
in two primary cell lines established from pediatric medulloblastoma patients
(MCH-BT-31 and MCH-BT-39), respectively.
Similarly, in the pediatric ependymoma
cell lines (MCH-BT-30 and MCH-BT-52), tamoxifen enhanced etoposide cytotoxicity
6- and 2.68-fold, respectively.
CalcuSyn analysis of cytotoxicity data showed
that tamoxifen and etoposide combinations were synergistic with combination
index values ranging from 0.243 to 0.369 at IC50 level among different pediatric
brain tumor cell lines.
Tamoxifen is also cytotoxic at higher concentrations
(> 20 microM) in brain tumor cells.
To understand the mechanism underlying
the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of
P-glycoprotein (P-gp), insulin-like growth factor-I receptor (IGF-IR), IGF-I,
IGF-II and estrogen receptor as well as protein kinase C (PKC) activity.
While
P-gp, IGF-IR and IGF-I were not affected, enhanced inhibition of PKC, and IGF-II
were observed in brain tumor cells treated with tamoxifen and etoposide
combination as compared to cells treated with either drug alone.
Tamoxifen at 10
microM when combined with etoposide at 0-100 microM concentrations reduced PKC
activity 77% compared to only 58% without tamoxifen.
IGF-II expression decreased
to 48.6% of the untreated control in the combination treatment as compared to
31.2% for etoposide alone and 26.2% for tamoxifen alone treatments.
These
results suggest that inhibitory effect of tamoxifen on brain tumor cells
manifest through different mechanisms involving inhibition of targets such as
PKC and IGF-II.
PMID: 15072444 [PubMed]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15072444
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