NF-kB inhibitors CAPE and MG-132 have selective apoptotic and antiproliferative 1

CAVALIERE V, PAPADEMETRIO D, LORENZETTI M,VALVA P, PRECIADO MV, GARGALLO P, LARRIPA I, MONREAL M; PARDO L, HAJOS SE, BLANCO G Y ALVAREZ E.

Translational Oncology

Neoplasia Press

Lugar: confirmar; Año: 2008 vol. 0 p. 1 - 10

Chemotherapy aims to limit proliferation and induce apoptotic cell death in tumor cells. Owing to blockade of signaling pathways involved in cell survival and proliferation, NF-kB kB inhibitors can induce apoptosis in a number of hematological malignancies. The efficacy of conventional chemotherapeutic drugs, such as Vincristine (VCR), and Doxorubicine (DOX), may be enhanced with combined therapy with NF-êB inhibitors. In this study, we evaluated êB inhibitors. In this study, we evaluated the effect of two NF-êB inhibitors, Caffeic Acid Phenylethyl Ester (CAPE) and MG-132, and êB inhibitors, Caffeic Acid Phenylethyl Ester (CAPE) and MG-132, and conventional chemotherapeutics drugs DOX and VCR on cell proliferation and apoptosis induction on a lymphoblastoid B cell line, PL104, established and characterized in our laboratory. CAPE and MG-132 treatment showed a strong antiproliferative effect accompanied by clear cell cycle deregulation and apoptosis induction. DOX and VCR showed antiproliferative effects similar to those of NF-êB inhibitors, although the latter êB inhibitors, although the latter showed an apoptotic rate 2 fold higher than DOX and VCR. None of the four compounds showed cytotoxic effect on peripheral mononuclear cells from healthy volunteers. CAPE- and MG-132-treated bone marrow cells from patients with myeloid and lymphoid leukemias showed 69% (p<0.001) and 25% decrease (p<0.01) in cell proliferation, and 42% and 34% (p<0.01) apoptosis induction respectively. Treatment of PL104 cells with sub-lethal concentrations of CAPE or MG-132 plus DOX or VCR resulted in enhanced apoptosis. Overall, our results indicate that CAPE and MG-132 had a strong and selective apoptotic effect on tumor cells that may be useful either alone or in combination with current anticancer agents. Abbreviations: CAPE, Caffeic Acid Phenylethyl Ester; DOX, Doxorubicine; EtBr, ethidium Abbreviations: CAPE, Caffeic Acid Phenylethyl Ester; DOX, Doxorubicine; EtBr, ethidium Abbreviations: CAPE, Caffeic Acid Phenylethyl Ester; DOX, Doxorubicine; EtBr, ethidium Abbreviations: CAPE, Caffeic Acid Phenylethyl Ester; DOX, Doxorubicine; EtBr, ethidium Abbreviations: CAPE, Caffeic Acid Phenylethyl Ester; DOX, Doxorubicine; EtBr, ethidium bromide; FCS, fetal calf serum; [3H]TdR, tritiated thymidine; NF-êB, Nuclear factor-êB; 3H]TdR, tritiated thymidine; NF-êB, Nuclear factor-êB; PBMCs, peripheral blood mononuclear cells; PDL, Patient-derived leukemic; VCR,