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J. Biol. Chem., Vol. 279, Issue 5, 3877-3884, January 30, 2004

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12-O-Tetradecanoylphorbol-13-acetate May Both Potentiate and Decrease the Generation of Apoptosis by the Antileukemic Agent Arsenic Trioxide in Human Promonocytic Cells

REGULATION BY EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASES AND GLUTATHIONE^*

Carlos Fernández, Adrián M. Ramos, Patricia Sancho¶, Donna Amrán, Elena de Blas, and Patricio Aller||

From the Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain

Arsenic trioxide (As₂O₃) caused apoptosis in U-937 human promonocytic cells. This effect was potentiated by the simultaneous addition of the glutathione (GSH) synthesis inhibitor DL-buthionine-(R,S)-sulfoximine or the protein kinase C activators 12-O-tetradecanoylphorbol-13-acetate (TPA) and bryostatin 1. In addition TPA decreased the intracellular GSH content, caused ERK activation, and potentiated the As₂O₃-provoked activation of p38 and JNK. The addition of N-acetyl-L-cysteine, the PKC inhibitor GF109203X, and the MEK/ERK inhibitors PD98059 and U0126 attenuated both apoptosis induction and GSH decrease, whereas the p38 inhibitor SB203580 and the JNK inhibitor SP600125 were ineffective. TPA also potentiated ERK activation and GSH depletion when added simultaneously to cadmium chloride (CdCl₂) and doxorubicin. However, TPA only enhanced apoptosis in the case of CdCl₂, which is a GSH-sensitive agent, whereas it reduced the toxicity of doxorubicin and other DNA-specific drugs. Finally, preincubation for 14-24 h with TPA did not potentiate but, instead, attenuated the As₂O₃- and CdCl₂-provoked apoptosis. The same result was obtained by preincubation with bryostatin 1 and other differentiation inducers. It is concluded that TPA increases the apoptotic action of As₂O₃, an effect mediated by ERK activation and GSH depletion. However, the increase in apoptosis is only effective in non-differentiated cells.

Received for publication, September 26, 2003 , and in revised form, November 7, 2003.

^* This work was supported by Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Ciencia y Tecnología Grant SAF2001-1219, Fondo de Investigación Sanitaria, Ministerio de Sanidad y Consumo Grant 01/0946, and Dirección General de Investigación, Comunidad de Madrid, Spain Grant 08.3/0011.3/2001. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a predoctoral fellowship from the Ministerio de Ciencia y Tecnología, Spain.

Recipient of a postdoctoral fellowship from the Fundación Carolina, Spain.

^¶ Recipient of a predoctoral fellowship from the Ministerio de Educación, Cultura y Deporte, Spain.

^|| To whom correspondence should be addressed: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. Tel.: 34-918373112 (ext. 4247); Fax: 34-915360432; E-mail: aller{at}cib.csic.es.

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