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¹ Institut National de la Santé et de la Recherche Médicale U612, Institut Curie-Recherche, Centre Universitaire, Orsay, France; ² Hôpital Saint-Louis, Radiothérapie-Oncologie, Paris, France; ³ Institut National de la Sante et de la Recherche Medicale U517, Faculté de Médecine, Université de Bourgogne, Dijon, France

Requests for reprints: Vincent Favaudon, INSERM, U612, Institut Curie-Recherche, Bât. 110-112, Centre Universitaire, 91405 Orsay Cedex, France. Phone: 33-1-6986-3188; Fax: 33-1-6986-3187. E-mail: vincent.favaudon{at}curie.u-psud.fr

Enhanced cytotoxicity of etoposide by wortmannin, an inhibitor of enzymes holding a phosphatidylinositol 3-kinase domain, was investigated in eight cell lines proficient or deficient for DNA double-strand break repair. Wortmannin stimulated the decatenating activity of topoisomerase II, promoted etoposide-induced accumulation of DNA double-strand breaks, shifted the specificity for cell killing by etoposide from the S to G₁ phase of the cell cycle, and potentiated the cytotoxicity of etoposide through two mechanisms. (a) Sensitization to high, micromolar amounts of etoposide required integrity of the nonhomologous end-joining repair pathway. (b) Wortmannin dramatically increased the susceptibility to low, submicromolar amounts of etoposide in a large fraction of the cell population irrespective of the status of ATM, Ku86, and DNA-PK_CS. It is shown that this process correlates depression of phosphatidylinositol 3-kinase–dependent phosphorylation of the atypical, isoform of protein kinase C (PKC). Stable expression of a dominant-negative, kinase-dead mutant of PKC in a tumor cell line reproduced the hypersensitivity pattern induced by wortmannin. The results are consistent with up-regulation of the topoisomerase II activity in relation to inactivation of PKC and indicate that PKC may be a useful target to improve the efficiency of topoisomerase II poisons at low concentration.

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Note: C. Reis is currently at the Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RR, United Kingdom.

M. Fernet is currently at the Institut de Biologie Structurale J.P. Ebel, 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France.

Received 5/17/05; revised 7/18/05; accepted 8/10/05.