Caffeic Acid Phenulethyl Ester and MG 132, two novel non-convenitonal chemotherapeutic agents, induce apoptosis of human leukemic cells by disrupting mitochondrial function.

CAVALIERE V.; PAPADEMETRIO D,; LOMBARDO T.,; COSTANTINO S.; BLANCO G; ALVAREZ E.

TARGETED ONCOLOGY

SPRINGER

Lugar: Berlin; Año: 2014 vol. 9 p. 25 - 42

1776-2596

The ability to modulate balance between cell survival and death is recognized for its great therapeutic potential. Therefore, research continues to focus on elucida- tion of cell machinery and signaling pathways that control cell proliferation and apoptosis. Conventional chemothera- peutic agents often have a cytostatic effect over tumor cells. New natural or synthetic chemotherapeutic agents have a wider spectrum of interesting antitumor activities that merit in-depth studies. In the present work, we aimed at charac- terizing the molecular mechanism leading to induction of cell death upon treatment of the lymphoblastoid cell line PL104 with caffeic acid phenylethyl ester (CAPE), MG132 and two conventional chemotherapeutic agents, doxorubicine (DOX) and vincristine (VCR). Our results showed several apoptotic hallmarks such as phosphatidylserine (PS) exposure on the outer leaflet of the cell membrane, nuclear fragmenta- tion, and increase sub-G1 DNA content after all treatments. In addition, all four drugs downregulated survivin expression. CAPE and both chemotherapeutic agents reduced Bcl-2, while only CAPE and MG132 significantly increased Bax level. CAPE and VCR treatment induced the collapse of mitochondrial membrane potential (Δψm). All compounds induced cytochrome c release from mitochondrial compart- ment to cytosol. However, only MG132 caused the transloca- tion of Smac/DIABLO. Except for VCR treatment, all other drugs increased reactive oxygen species (ROS) production level. All treatments induced activation of caspases 3/7, but only CAPE and MG132 led to the activation of caspase 9. In conclusion, our results indicate that CAPE and MG132 treat- ment of PL104 cells induced apoptosis through the mitochon- drial intrinsic pathway, whereas the apoptotic mechanism induced by DOX and VCR may proceed through the extrinsic pathway