Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expressio

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Tolfenamic acid enhances pancreatic cancer cell and tumor response
to radiation therapy by inhibiting survivin protein expression.

 
Konduri S, Colon J, Baker CH, Safe S, Abbruzzese JL, Abudayyeh A, Basha MR, Abdelrahim M.
 
Cancer Research Institute, M. D. Anderson Cancer Center Orlando, 110 Bonnie Loch Court, Mail Point 47, Orlando, FL 32806, USA.
 
Survivin
is overexpressed in most human cancers, including pancreatic
adenocarcinoma. Expression of survivin is regulated by specificity
protein (Sp) proteins and related to resistance to radiation therapy.
Tolfenamic acid induces Sp protein degradation in several cancer cell
lines. The purpose of this study is to investigate whether tolfenamic
acid inhibits survivin expression and sensitizes pancreatic cancer
cells/tumor to radiotherapy. Panc1 and L3.6pl cells have been used to
study the effect of radiation on survivin expression and to investigate
the efficacy of tolfenamic acid in enhancing the response to radiation
therapy. In addition, an orthotopic model for human pancreatic cancer
has been used to confirm the efficacy of tolfenamic acid to enhance
tumor response to radiation in vivo. Pancreatic cancer cell lines
express variable levels of survivin mRNA/protein, which correlate with
their radiosensitivity. Radiation increased survivin promoter activity
and protein expression in Panc1 and L3.6pl cells and tolfenamic acid
inhibited both constitutive and radiation-induced survivin protein
expression and enhanced the response of pancreatic cancer cells to
radiation therapy. In vivo studies show that tolfenamic acid enhanced
the radiation-induced apoptosis associated with decreased survivin
expression in tumors and this correlates with the enhanced response of
these tumors to the radiation. Thus, tolfenamic acid significantly
enhances pancreatic cancer cells/tumor response to radiation therapy.
The underlying mechanism includes tolfenamic acid-induced degradation
of Sp proteins, which in tumor decreases expression of the Sp-dependent
antiapoptotic protein survivin. These preclinical data suggest that
tolfenamic acid has the potential to increase the response of
pancreatic adenocarcinoma to radiation therapy.