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Anticancer Res. 2007 Sep-Oct;27(5A):3075-82.

Doxorubicin and selenium cooperatively induce fas signaling in the absence of Fas/Fas ligand interaction.

Author information

1
Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Abstract

BACKGROUND:

The synergistic effect of doxorubicin and selenium in apoptosis induction in MCF-7 breast cancer cells has been previously reported. Mitochondrial activation of caspase-9 is in part responsible for the synergy. The present study aimed at examining the death receptor pathway in activating caspase-8 by the two-drug combination.

MATERIALS AND METHODS:

We determined the expression of TRAIL and FasL signaling molecules and monitored activated caspase-8 in response to neutralizing/blocking antibodies against ligands/receptors.

RESULTS:

Our data suggest that TRAIL signaling might not play a role. With respect to the Fas pathway, it was found that doxorubicin enhanced Fas oligomerization (i.e. activation) independent of FasL-Fas interaction. Selenium, on the other hand, increased the expression of FADD, a key adaptor molecule responsible for recruitment of caspase-8 to the Fas oligomer. The significance of the above changes was confirmed by the detection of considerably more caspase-8 in both the Fas or FADD immunoprecipitate obtained from cells treated with the doxorubicin/selenium combination.

CONCLUSION:

Doxorubicin and selenium cooperatively activate Fas signaling by targeting key regulatory steps.

PMID:
17970047
[Indexed for MEDLINE]
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