MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts.
The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (OBD). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM.
Vallet
Sonia
S
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Raje
Noopur
N
Ishitsuka
Kenji
K
Hideshima
Teru
T
Podar
Klaus
K
Chhetri
Shweta
S
Pozzi
Samantha
S
Breitkreutz
Iris
I
Kiziltepe
Tanyel
T
Yasui
Hiroshi
H
Ocio
Enrique M
EM
Shiraishi
Norihiko
N
Jin
Janice
J
Okawa
Yutaka
Y
Ikeda
Hiroshi
H
Mukherjee
Siddhartha
S
Vaghela
Nileshwari
N
Cirstea
Diana
D
Ladetto
Marco
M
Boccadoro
Mario
M
Anderson
Kenneth C
KC
D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D016762:Genes, fos; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*
D054405:Chemokine CCL3; D054389:Receptors, CCR1
Blood. 2000 Jul 15;96(2):671-5
10887133
Blood. 1995 Oct 15;86(8):3151-9
7579410
Blood. 2001 Jun 1;97(11):3349-53
11369623
J Clin Invest. 2001 Dec;108(12):1833-41
11748267
Hematol J. 2001;2(1):42-53
11920233
Blood. 2002 Jun 15;99(12):4646-7; author reply 4647
12066787
J Cell Biol. 1996 Aug;134(4):1063-73
8769427
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10939-44
8855287
J Bone Miner Res. 2004 Dec;19(12):2065-77
15537451
Exp Hematol. 2005 Mar;33(3):272-8
15730850
Br J Cancer. 2005 Apr 25;92(8):1531-7
15812559
Blood. 2005 Jul 15;106(2):713-6
15817674
Ann N Y Acad Sci. 2005 Jun;1051:647-57
16127005
Oncogene. 2005 Sep 1;24(38):5897-904
16007209
J Bone Miner Res. 2006 Jan;21(1):48-57
16355273
J Biol Chem. 2006 Jan 13;281(2):1274-85
16280328
J Cell Biochem. 2006 Feb 15;97(3):512-8
16211583
N Engl J Med. 2006 Feb 9;354(6):610-21
16467548
Clin Exp Metastasis. 2006;23(1):9-18
16821125
Clin Exp Metastasis. 2006;23(5-6):291-300
17086356
J Cell Biochem. 2007 May 1;101(1):122-34
17171644
Blood. 2007 Jul 15;110(2):709-18
17384201
Nat Cell Biol. 2002 Aug;4(8):556-64
12134156
Blood. 2002 Sep 15;100(6):2195-202
12200385
J Cell Biochem. 2002;87(4):386-93
12397598
J Biol Chem. 2002 Oct 25;277(43):41147-56
12171919
Leukemia. 2003 Jan;17(1):203-10
12529679
Cancer. 2003 Feb 1;97(3 Suppl):859-65
12548587
J Clin Invest. 2003 Mar;111(5):749-58
12618529
Br J Cancer. 2003 Mar 24;88(6):855-62
12644822
Blood. 2003 May 1;101(9):3568-73
12506012
Blood. 2003 Jul 1;102(1):311-9
12649140
Eur J Immunol. 2004 Mar;34(3):785-95
14991608
Biochem Biophys Res Commun. 2004 Apr 2;316(2):573-9
15020256
J Biol Chem. 2004 Aug 6;279(32):33567-74
15136564
Blood. 2004 Oct 15;104(8):2484-91
15187021
Science. 1994 Oct 21;266(5184):443-8
7939685
J Exp Med. 2000 Aug 21;192(4):495-506
10952719