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Targeting aurora kinases as therapy in multiple myeloma.
Shi, Yijiang; Reiman, Tony; Li, Weiqun; Maxwell, Christopher A; Sen, Subrata; Pilarski, Linda; Daniels, Tracy R; Penichet, Manuel L; Feldman, Rick; Lichtenstein, Alan.
Afiliación
  • Shi Y; Division of Hematology, Veterans Administration West Los Angeles-UCLA Medical School and Jonsson Cancer Center, University of California-Los Angeles, CA, USA.
Blood ; 109(9): 3915-21, 2007 May 01.
Article en En | MEDLINE | ID: mdl-17213289
The aurora kinases facilitate transit from G2 through cytokinesis and, thus, are targets in cancer therapy. Multiple myeloma (MM) is a malignancy characterized by genetic instability, suggesting a disruption of checkpoints that arrest cells at G2M when injury to the mitotic machinery occurs. Since deficient checkpoints would prevent cell cycle arrest and may render cells susceptible to apoptosis in mitosis and since aurora kinases are intermediaries in checkpoint pathways, we tested antimyeloma effects of 2 agents that inhibit aurora kinases. Both inhibited growth of MM lines and primary myeloma samples at nanomolar concentrations while having less of an effect on proliferating lymphocytes and hematopoietic cells. MM cells were not protected by IL-6 or activating mutations of Ras. Antimyeloma effects included induction of tetraploidy followed by apoptosis. Apoptosis correlated with inhibition of aurora activity as shown by reduction of histone 3B phosphorylation. Ectopic expression of aurora A protected MM cells against aurora inhibitors but had no effect on apoptosis induced by bortezomib. As expression of RHAMM in MM contributes to genetic instability, we tested effects of RHAMM. RHAMM overexpression enhanced sensitivity to apoptosis and RHAMM silencing decreased sensitivity. These results suggest potential for aurora kinase inhibitors in MM especially in patients in whom RHAMM is overexpressed.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fase G2 / Proteínas Serina-Treonina Quinasas / Inhibidores de Proteínas Quinasas / Mieloma Múltiple Idioma: En Revista: Blood Año: 2007 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fase G2 / Proteínas Serina-Treonina Quinasas / Inhibidores de Proteínas Quinasas / Mieloma Múltiple Idioma: En Revista: Blood Año: 2007 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos