BUTHIONINE-S,R-SULFOXIMINE POTENTIATES GROWTH INHIBITION INDUCED BY 1,25(OH)2D3 ON BREAST CANCER CELLS WITH DIFFERENT PHENOTYPES

MARCHIONATTI A; BOHL L; LIAUDAT A; PICOTTO G; RODRÍGUEZ V; NARVAEZ C; WELSH J; TOLOSA DE TALAMONI NG

Congreso; XXIX Reunión Anual de la Asociación Argentina de Osteología y Metabolismo Mineral; 2012

1,25(OH)2D3 induces antiproliferative effects on breast cancer tumors withundesired hypercalcemia. Combination of calcitriol with glutathione-depleting drugs,such as buthionine-S,R-sulfoximine (BSO), may enhance the steroid effects andovercome hypercalcemia. Previously we demonstrated that BSO enhanced the steroidantiproliferative action on MCF-7 breast cancer cells inducing ROS production andarresting cells in G1 phase (Bohl. et al., Cancer Inv., in press, 2012). Our aim was todeepen in the molecular mechanisms involved and to extend our study to other breastcancer cell lines. MCF-7, MCF-7DR (resistant to calcitriol) and HMLER (triple negative)cells were treated with 100 nM calcitriol, 20 ìM BSO or both for 4 days. Cell growthwas evaluated by crystal violet staining; superoxide dismutase (SOD) activity byspectophotometry; caspase activation by fluorescence microscopy; Bcl2 geneexpression by RT-qPCR. Results were analyzed using ANOVA and Bonferroni test.BSO, 1,25(OH)2D3 and their combination inhibited cell viability in MCF-7 and HMLERcell lines being the later more sensitive to BSO. Calcitriol and/or BSO have minimaleffects on MCF-7DR cells. SOD activity was induced with calcitriol and was higherwith the co-treatment. The combined treatment induced caspase activation andreduced the antiapoptotic Bcl2 gene relative expression. Altogether, the potentiationof 1,25(OH)2D3 inhibitory effect on MCF-7 cell growth by the combined treatment isprovoked by an alteration in the redox status and induction of apoptosis. Thecombination may be useful to reduce hypercalcemia and to be applied on calcitriolresistantcells or triple negative mammary tumors.