Combination of doxorubicin and sulforaphane for reversing doxorubicin-resistant phenotype in mouse fibroblasts with p53Ser220 mutation.
Chemoresistance in cancer therapy is a multifactorial process, which includes alterations in drug accumulation, increased activity of gluthatione S-transferases, loss of function, and mutations of p53, etc. One strategy for reversing chemoresistance is the use of chemopreventive agents alongside standard chemotherapeutic protocols. Sulforaphane is one of the most promising chemopreventive agents. Sulforaphane inhibits cell proliferation and induces apoptosis in different tumor cell lines. Its proapoptotic potential could make it effective either alone or in combination with other therapeutic strategies in reversing chemoresistance. We investigated the effects of sulforaphane on mouse fibroblasts bearing a different p53 status (wild-type, knockout, mutated) for understanding whether its activity is prevented by a mutated p53 status. p53-knockout fibroblasts from newborn mice transfected with the p53(Ser220) mutation, observed in different human cancers, were used as a model of mutated p53 status. Moreover, since p53(Ser220) mutation fibroblasts showed a doxorubicin-resistant phenotype, we treated the cells with a combination of doxorubicin plus 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. The association of sulforaphane-doxorubicin may therefore allow doxorubicin to be administered at lower doses, thereby reducing its potential toxicity.
Fimognari
Carmela
C
Department of Pharmacology, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy. carmela.fimognari@unibo.it
Lenzi
Monia
M
Sciuscio
Davide
D
Cantelli-Forti
Giorgio
G
Hrelia
Patrizia
P
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002460:Cell Line; D002461:Cell Line, Transformed; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012694:Serine / Q000235:genetics; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D016159:Tumor Suppressor Protein p53; D012694:Serine; D004317:Doxorubicin; C016766:sulforaphane