Caffeic acid phenylethyl ester and MG132, two novel nonconventional chemotherapeutic agents, induce apoptosis of human leukemic cells by disruptingmitochondrial function.

VICTORIA CAVALIERE, DANIELA L. PAPADEMETRIO, TOMÁS LOMBARDO, SUSANA N. COSTANTINO, GUILLERMO A. BLANCO & ELIDA M. C. ÁLVAREZ

TARGETED ONCOLOGY

SPRINGER

Año: 2014 vol. 9 p. 25 - 42

1776-2596

The ability to modulate balance between cellsurvival and death is recognized for its great therapeuticpotential. Therefore, research continues to focus on elucidationof cell machinery and signaling pathways that controlcell proliferation and apoptosis. Conventional chemotherapeuticagents often have a cytostatic effect over tumor cells.New natural or synthetic chemotherapeutic agents have awider spectrum of interesting antitumor activities that meritin-depth studies. In the present work, we aimed at characterizingthe molecular mechanism leading to induction ofcell death upon treatment of the lymphoblastoid cell linePL104 with caffeic acid phenylethyl ester (CAPE), MG132and two conventional chemotherapeutic agents, doxorubicine(DOX) and vincristine (VCR). Our results showed severalapoptotic hallmarks such as phosphatidylserine (PS) exposureon the outer leaflet of the cell membrane, nuclear fragmentation,and increase sub-G1 DNA content after all treatments. Inaddition, all four drugs downregulated survivin expression.CAPE and both chemotherapeutic agents reduced Bcl-2,while only CAPE and MG132 significantly increased Baxlevel. CAPE and VCR treatment induced the collapse ofmitochondrial membrane potential (Δψm). All compoundsinduced cytochrome c release from mitochondrial compartmentto cytosol. However, only MG132 caused the translocationof Smac/DIABLO. Except for VCR treatment, all otherdrugs increased reactive oxygen species (ROS) productionlevel. All treatments induced activation of caspases 3/7, butonly CAPE and MG132 led to the activation of caspase 9. Inconclusion, our results indicate that CAPE and MG132 treatmentof PL104 cells induced apoptosis through the mitochondrialintrinsic pathway, whereas the apoptotic mechanisminduced by DOX and VCR may proceed through the extrinsicpathway.