A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma.
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.
Görgün
Güllü
G
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. gullu_gorgun@dfci.harvard.edu
Calabrese
Elisabetta
E
Hideshima
Teru
T
Ecsedy
Jeffrey
J
Perrone
Giulia
G
Mani
Mala
M
Ikeda
Hiroshi
H
Bianchi
Giada
G
Hu
Yiguo
Y
Cirstea
Diana
D
Santo
Loredana
L
Tai
Yu-Tzu
YT
Nahar
Sabikun
S
Zheng
Mei
M
Bandi
Madhavi
M
Carrasco
Ruben D
RD
Raje
Noopur
N
Munshi
Nikhil
N
Richardson
Paul
P
Anderson
Kenneth C
KC
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
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
Blood. 2009 May 21;113(21):5228-36
19270264
Leuk Lymphoma. 2008 Mar;49(3):559-69
18297535
J Med Chem. 2009 May 14;52(9):2629-51
19320489
J Cell Biol. 2003 Apr 28;161(2):267-80
12719470
Cell. 2003 Sep 5;114(5):585-98
13678582
Cell Cycle. 2009 Mar 15;8(6):876-88
19221504
Blood. 2009 Apr 30;113(18):4331-40
19171872
Biol Cell. 2004 Apr;96(3):215-29
15182704
Neoplasia. 2009 May;11(5):418-25
19412426
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11
17360485
Cancer Res. 2009 Sep 15;69(18):7207-15
19738056
J Med Chem. 2005 Apr 21;48(8):3080-4
15828847
Br J Haematol. 2009 Dec;147(5):672-6
19751238
Blood. 2008 Feb 1;111(3):1603-9
18006703
Blood. 2007 May 1;109(9):3915-21
17213289
Blood. 2003 Oct 1;102(7):2562-7
12805059
Nat Rev Cancer. 2007 Aug;7(8):585-98
17646864
Curr Biol. 2003 Apr 15;13(8):691-7
12699628
Oncogene. 2006 Feb 16;25(7):1053-69
16205633
Mol Cell. 1999 Jan;3(1):119-23
10024885
Oncogene. 2006 Dec 14;25(59):7691-702
16785988
Eur J Cancer. 2006 Jul;42(11):1564-73
16765041
J Cell Biol. 2001 Dec 24;155(7):1109-16
11748251
Mol Cancer Ther. 2009 Aug;8(8):2461-9
19671766
Cancer Cell. 2004 Feb;5(2):191-9
14998494
Leukemia. 1998 Jun;12(6):960-9
9639426
Adv Enzyme Regul. 1984;22:27-55
6382953
Int J Biochem Cell Biol. 2005 Aug;37(8):1572-7
15896667
Nat Cell Biol. 2003 Mar;5(3):242-8
12577065
Blood. 2009 Sep 24;114(13):2699-708
19652203
Br J Cancer. 2008 Feb 12;98(3):523-8
18231106
Blood. 2005 Jul 1;106(1):296-303
15755896
Blood. 2008 Sep 15;112(6):2439-49
18614762
J Cell Sci. 1999 Nov;112 ( Pt 21):3591-601
10523496
J Hematop. 2009 Mar;2(1):2-8
19669217
Cancer Res. 2007 Jun 1;67(11):5362-70
17545617
Genes Cells. 2002 Nov;7(11):1173-82
12390251
J Cell Biol. 2003 Apr 28;161(2):281-94
12707311
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8625-30
15173575
Br J Haematol. 2008 Feb;140(3):295-302
18076711
J Biol Chem. 2000 Feb 25;275(8):5600-5
10681541
J Natl Cancer Inst. 2002 Sep 4;94(17):1320-9
12208897
Nat Rev Mol Cell Biol. 2001 Jan;2(1):21-32
11413462