Targeting aurora kinases as therapy in multiple myeloma Export

@article{citeulike:3078573, abstract = {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. 10.1182/blood-2006-07-037671}, author = {Shi, Yijiang and Reiman, Tony and Li, Weiqun and Maxwell, Christopher A. and Sen, Subrata and Pilarski, Linda and Daniels, Tracy R. and Penichet, Manuel L. and Feldman, Rick and Lichtenstein, Alan}, citeulike-article-id = {3078573}, citeulike-linkout-0 = {http://dx.doi.org/10.1182/blood-2006-07-037671}, citeulike-linkout-1 = {http://bloodjournal.hematologylibrary.org/cgi/content/abstract/109/9/3915}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17213289}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17213289}, doi = {10.1182/blood-2006-07-037671}, journal = {Blood}, keywords = {20q, aurka, pancreatic}, month = {May}, number = {9}, pages = {3915--3921}, posted-at = {2008-08-03 16:27:39}, priority = {2}, title = {Targeting aurora kinases as therapy in multiple myeloma}, url = {http://dx.doi.org/10.1182/blood-2006-07-037671}, volume = {109}, year = {2007} }

TY - JOUR ID - citeulike:3078573 L3 - citeulike-article-id:3078573 N2 - 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. 10.1182/blood-2006-07-037671 IS - 9 JF - Blood EP - 3921 TI - Targeting aurora kinases as therapy in multiple myeloma VL - 109 SP - 3915 KW - 20q KW - aurka KW - pancreatic AU - Shi, Yijiang AU - Reiman, Tony AU - Li, Weiqun AU - Maxwell, Christopher AU - Sen, Subrata AU - Pilarski, Linda AU - Daniels, Tracy AU - Penichet, Manuel AU - Feldman, Rick AU - Lichtenstein, Alan PY - 2007/05/01/ UR - http://dx.doi.org/10.1182/blood-2006-07-037671 ER -