INVESTIGADORES
ALVAREZ Elida Maria Del Carmen
artículos
Título:
Synergism between arsenite and proteasome inhibitor MG132 over cell death in myeloid leukaemic cells U937 and the induction of low levels of intracellular superoxide anion.
Autor/es:
CAVALIERE V; COSTANTINO S.; KOMBLIHTT L; ALVAREZ E.; BLANCO G.
Revista:
TOXICOLOGY AND APPLIED PHARMACOLOGY
Editorial:
ACADEMIC PRESS INC ELSEVIER SCIENCE
Referencias:
Lugar: Amsterdam; Año: 2012 vol. 258 p. 351 - 366
ISSN:
0041-008X
Resumen:
ncreased oxygen species production has often been cited as a mechanism
determining synergism on cell death and growth inhibition effects of
arsenic-combined drugs. However the net effect of drug combination may
not be easily anticipated solely from available knowledge of
drug-induced death mechanisms. We evaluated the combined effect of
sodium arsenite with the proteasome inhibitor MG132, and the
anti-leukaemic agent CAPE, on growth-inhibition and cell death effect in
acute myeloid leukaemic cells U937 and Burkitt's lymphoma-derived Raji
cells, by the Chou-Talalay method. In addition we explored the
association of cytotoxic effect of drugs with changes in intracellular
superoxide anion (O₂⁻) levels. Our results showed that combined
arsenite+MG132 produced low levels of O₂⁻ at 6h and 24h after exposure
and were synergic on cell death induction in U937 cells over the whole
dose range, although the combination was antagonistic on growth
inhibition effect. Exposure to a constant non-cytotoxic dose of 80μM
hydrogen peroxide together with arsenite+MG132 changed synergism on cell
death to antagonism at all effect levels while increasing O₂⁻ levels.
Arsenite+hydrogen peroxide also resulted in antagonism with increased
O₂⁻ levels in U937 cells. In Raji cells, arsenite+MG132 also produced
low levels of O₂⁻ at 6h and 24h but resulted in antagonism on cell death
and growth inhibition. By contrast, the combination arsenite+CAPE
showed high levels of O₂⁻ production at 6h and 24 h post exposure but
resulted in antagonism over cell death and growth inhibition effects in
U937 and Raji cells. We conclude that synergism between arsenite and
MG132 in U937 cells is negatively associated to O₂⁻ levels at early time
points after exposure.