Targeted Therapy of Acute Myeloid Leukemia by Michael Andreeff

Author:Michael Andreeff
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

20.1.2 Aurora Kinase Inhibitors in Clinical Development

The awareness that Aurora kinases were aberrantly expressed in malignancies and were involved in tumorigenesis led to the development of a large number of Aurora kinase inhibitors (AKIs) for cancer therapy . Early studies revealed insights into the molecular consequences of Aurora A inhibition in cancer cells. Microinjection of Aurora A antibodies and/or RNAi-mediated knockdown of Aurora A kinase led G2/M arrest, growth inhibition, and apoptosis (Hirota et al. 2003; Hata et al. 2005; Marumoto et al. 2002). Other consequences of targeted Aurora A inhibition include disruption of multiple mitotic events, culminating in failure of centrosome separation, monopolar spindle formation, and incomplete cytokinesis (Marumoto et al. 2003). On the other hand, RNAi-mediated inhibition of Aurora B expression disrupts chromosomal biorientation, cytokinesis, and the mitotic checkpoint (Goto et al. 2003; Severson et al. 2000). Abrogation of the mitotic checkpoint allows cells to go through multiple cycles of aberrant mitosis without cytokinesis resulting in massive polyploidy leading to cell death by mitotic catastrophe (Nair et al. 2009; Hauf et al. 2003). In the light of these multiple molecular sequelae, AKIs may be selectively more toxic to rapidly dividing cancer cells over nondividing cells .

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