Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 29
Combination of doxorubicin and sulforaphane for reversing doxorubicin-resistant
phenotype in mice fibroblasts with p53Ser220 mutation
Carmela Fimognari, Giorgio Cantelli-Forti, Patrizia Hrelia.
Department of Pharmacology, University of Bologna, Bologna, Italy. E-mail:
carmela.fimognari@unibo.it
Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid
malignancies. The major factor that limits the effectiveness of chemotherapy in patients with
advanced cancer is the acquisition of resistance. Chemoresistance is a multifactorial process,
which includes alterations in drug accumulation, increased activity of gluthatione Stransferases,
loss of function and mutations of p53, etc. One strategy for reversing drug
resistance is the concomitant use of chemopreventive agents (i.e. non-cytotoxic agents able to
block the progression to invasive cancer) that are by themselves non-toxic but that cause a
better response rates than either reagent alone. Sulforaphane is one of the most promising
chemopreventive agent. Sulforaphane inhibits cell-cycle progression and induces apoptosis in
different tumor cell lines. The pro-apoptotic potential of sulforaphane could be effective
either alone or in combination with other therapeutic strategies in reversing chemoresistance.
We firstly investigated the effects of sulforaphane on mouse fibroblasts bearing a different
p53 status (wild-type, knock-out, mutated) for understanding whether its activity is prevented
by a mutated p53 status. p53-knock-out fibroblasts from newborn mice transfected with the
p53Ser220 mutation, observed in different human cancers, were used as a model of mutated
p53 status. Moreover, since p53Ser220 mutation fibroblasts showed a doxorubicin-resistant
phenotype, we secondly treated the cells with a combination of doxorubicin plus
sulforaphane. To clarify the optimal schedule of combination, we studied the effects of
simultaneous and sequential exposure to doxorubicin and sulforaphane. Taken together, our
results suggest that a mutated p53 status did not prevent the induction of apoptosis by
sulforaphane and that sulforaphane was able to reverse the resistance to doxorubicin when
administered simultaneously or after doxorubicin. The association sulforaphane-doxorubicin
may therefore allow doxorubicin to be administered at lower doses, thereby reducing its
potential toxicity.
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