title: A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma.
abstract: Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. gullu_gorgun@dfci.harvard.edu
authors.forename: Güllü
authors.initials: G
authors.lastname: Görgün
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Calabrese
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ecsedy
authors.forename: Giulia
authors.initials: G
authors.lastname: Perrone
authors.forename: Mala
authors.initials: M
authors.lastname: Mani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Giada
authors.initials: G
authors.lastname: Bianchi
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Hu
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Sabikun
authors.initials: S
authors.lastname: Nahar
authors.forename: Mei
authors.initials: M
authors.lastname: Zheng
authors.forename: Madhavi
authors.initials: M
authors.lastname: Bandi
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Carrasco
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011719:Pyrazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D008941:Spindle Apparatus / Q000378:metabolism; D013997:Time Factors; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D001381:Azepines; D001897:Boronic Acids; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases
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