NSC logoThe cost of publication in Journal of Biomedical Science is borne by the National Science Council, Taiwan.

Open Access Highly Accessed Research

Pentoxifylline and the proteasome inhibitor MG132 induce apoptosis in human leukemia U937 cells through a decrease in the expression of Bcl-2 and Bcl-XL and phosphorylation of p65

Alejandro Bravo-Cuellar12, Georgina Hernández-Flores1, José Manuel Lerma-Díaz12, Jorge Ramiro Domínguez-Rodríguez13, Luis F Jave-Suárez1, Ruth De Célis-Carrillo1, Adriana Aguilar-Lemarroy1, Paulina Gómez-Lomeli14 and Pablo Cesar Ortiz-Lazareno1*

Author Affiliations

1 División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, Guadalajara, Jalisco 44340, México

2 Departamento Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos, Jalisco, México

3 Departamento de Farmacobiología, Centro Universitario de Ciencias Exactas e Ingeniería, Universidad de Guadalajara, Guadalajara, Jalisco, México

4 Programa de Doctorado en Ciencias Biomédicas Orientación Inmunología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, 44340, México

For all author emails, please log on.

Journal of Biomedical Science 2013, 20:13  doi:10.1186/1423-0127-20-13

Published: 28 February 2013

Abstract

Background

In Oncology, the resistance of the cancerous cells to chemotherapy continues to be the principal limitation. The nuclear factor-kappa B (NF-κB) transcription factor plays an important role in tumor escape and resistance to chemotherapy and this factor regulates several pathways that promote tumor survival including some antiapoptotic proteins such as Bcl-2 and Bcl-XL. In this study, we investigated, in U937 human leukemia cells, the effects of PTX and the MG132 proteasome inhibitor, drugs that can disrupt the NF-κB pathway. For this, we evaluated viability, apoptosis, cell cycle, caspases-3, -8, -9, cytochrome c release, mitochondrial membrane potential loss, p65 phosphorylation, and the modification in the expression of pro- and antiapoptotic genes, and the Bcl-2 and Bcl-XL antiapoptotic proteins.

Results

The two drugs affect the viability of the leukemia cells in a time-dependent manner. The greatest percentage of apoptosis was obtained with a combination of the drugs; likewise, PTX and MG132 induce G1 phase cell cycle arrest and cleavage of caspases -3,-8, -9 and cytochrome c release and mitochondrial membrane potential loss in U937 human leukemia cells. In these cells, PTX and the MG132 proteasome inhibitor decrease p65 (NF-κB subunit) phosphorylation and the antiapoptotic proteins Bcl-2 and Bcl-XL. We also observed, with a combination of these drugs overexpression of a group of the proapoptotic genes BAX, DIABLO, and FAS while the genes BCL-XL, MCL-1, survivin, IκB, and P65 were downregulated.

Conclusions

The two drugs used induce apoptosis per se, this cytotoxicity was greater with combination of both drugs. These observations are related with the caspases -9, -3 cleavage and G1 phase cell cycle arrest, and a decrease in p65 phosphorylation and Bcl-2 and Bcl-XL proteins. As well as this combination of drugs promotes the upregulation of the proapoptotic genes and downregulation of antiapoptotic genes. These observations strongly confirm antileukemic potential.

Keywords:
U937; Apoptosis-related genes; Caspases; p65 phosphorylation; Bcl-2; Bcl-XL; pentoxifylline; MG132