Synergism of arsenic trioxide and MG132 in Raji cells attained by targeting BNIP3, autophagy, and mitochondria with low doses of valproic acid and vincristine.

V CAVALIERE; LOMBARDO TOMÁS; COSTANTINO SUSANA N; KORNBLIHTT LAURA; ALVAREZ ELIDA M; BLANCO GUILLERMO A

EUROPEAN JOURNAL OF CANCER

ELSEVIER SCI LTD

Lugar: Amsterdam; Año: 2014 vol. 50 p. 3243 - 3261

0959-8049

We previously demonstrated that arsenic trioxide (ATO) and proteasome inhibitor MG132 synergistically induced cell death in promonocytic leukaemia cell line U937 but were ntagonistic in Burkitt?s lymphoma cell line Raji. Here we explore the role of autophagy, xpression of BNIP3, and mitochondrial mass, in determining whether ATO and MG132 nteraction can be shifted from antagonism to synergism in Raji cells. Treatment with ATO + MG132 increased the percentage of cells with collapsed mitochondrial membrane otential (MMP) in U937 cells, but had no effect in Raji cells. Mitochondria were found in ytoplasmic marginal location in U937 cells but at perinuclear location in Raji cells. ATO + MG132 increased mitochondrial mass in U937 cells but decreased it in Raji cells, while autophagy was increased in both cell lines. BNIP3 was expressed in U937 cells at cytolasmic marginal locations and was hardly detected in Raji cells. Histone deacetylase (HDAC)nhibitor valproic acid (VPA) increased expression of BNIP3 in Raji cells at perinuclear locaions. However antagonism between ATO and MG132 was increased in the presence of low oses of VPA. Addition of vincristine (VCR) blocked autophagy, while VPA + VCR treatment of Raji cells at sub-cytotoxic doses caused BNIP3 and mitochondria to distribute oytoplasmic peripheral location and increased mitochondrial mass. ATO + MG132 in the resence of subcytotoxic doses of VPA + VCR caused collapse of MMP in Raji cells, while interaction between ATO and MG132 shifted from antagonism to synergism. We conclude that synergism between ATO and MG132 was attained in Raji cells by disruption of the perinuclear mitochondrial cluster, blockage of selective autophagy of mitochondria (mitophagy)by VCR, increased mitochondrial mass, and upregulation of BNIP3 by VPA.