SYNERGISM BETWEEN ARSENIC TRIOXIDE AND MG132 ACHIEVED WITH LOW DOSES OF VALPROIC ACID AND VINCRISTINE

KORNBLIHTT LAURA; LOMBARDO TOMÁS; CAVALIERE VICTORIA; ALVAREZ ELIDA; BLANCO GUILLERMO

Milán, Italia

Congreso; 19th Congress of the European Hematology Association; 2014

European Hematology Association

Background: Arsenic trioxide (ATO) has low efficacy as a single cytotoxic drugin malignancies other than promielocytic leukaemia but may be combined withother drugs to achieve increased potency and reduced toxicity. The study ofcytotoxic drugs interaction is an important aspect in the efficient design of targetedcombined therapies. The method of combinatory index (CI) allows the qualificationand quantification of drug interaction as synergic (CI<1), antagonistic (CI>1) oradditive (CI=1) over the entire range of cytotoxic effects [0-100%]. ATO andMG132, a proteasome inhibitor that targets chemotrypsin-like activity as doesBortezomib, are antagonistic in Burkitt´s lymphoma cell line Raji.Aims:We explored the possibility of changing the interaction between ATO andMG132 from antagonistic to synergic by adding subcytotoxic doses of twoadditional drugs: valproic acid (VPA) that targets histone deacetylase (HDAC),and vincristine (VCR) that disrupts the microtubule network. VPA upregulatesBNIP3, a Bcl2 family member that is epigenetically silenced in varioushaematological malignancies and has a controversial role in autophagy and celldeath.