SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis.
OBJECTIVE
Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action.


METHODS
The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo.


RESULTS
SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment.


CONCLUSIONS
These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma.
Department of Pathology, Center for Metabolic Bone Disease, and Comprehensive Cancer Center, University of Alabama at Birmingham, Alabama 35294, USA.
Joseph P
JP
Ritchie
Vishnu C
VC
Ramani
Yongsheng
Y
Ren
Annamaria
A
Naggi
Giangiacomo
G
Torri
Benito
B
Casu
Sergio
S
Penco
Claudio
C
Pisano
Paolo
P
Carminati
Monica
M
Tortoreto
Franco
F
Zunino
Israel
I
Vlodavsky
Ralph D
RD
Sanderson
Yang
Y
Yang
D000818:Animals; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006493:Heparin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D053668:Syndecan-1 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099175:Heparanase
D003907:Dexamethasone; D005966:Glucuronidase; D006493:Heparin; D017228:Hepatocyte Growth Factor; D020780:Matrix Metalloproteinase 9; D053668:Syndecan-1; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C559639:SST 0001
Blood. 2000 Nov 1;96(9):3139-46
11049995
Cancer Res. 2003 Sep 1;63(17):5224-9
14500349
Cardiovasc Drug Rev. 2004 Spring;22(1):1-6
14978514
Blood. 1993 Feb 1;81(3):767-74
8427968
Cancer Res. 2006 Feb 1;66(3):1455-63
16452201
J Med Chem. 2005 Dec 29;48(26):8229-36
16366604
Clin Exp Metastasis. 2008;25(2):149-59
18027090
FASEB J. 2007 Nov;21(13):3562-72
17557930
Blood. 2005 Feb 15;105(4):1383-95
15471951
J Immunol. 1992 Jun 15;148(12):3902-11
1602136
J Cell Biochem. 2005 Dec 1;96(5):897-905
16149080
Blood Coagul Fibrinolysis. 2007 Oct;18(7):595-8
17890944
Blood. 2002 Feb 15;99(4):1405-10
11830493
Curr Protoc Cell Biol. 2001 May;Chapter 10:Unit 10.4
18228298
Blood. 2008 Mar 1;111(5):2516-20
17975015
J Biol Chem. 2005 Apr 1;280(13):12103-13
15647251
Cancer Res. 2003 Dec 15;63(24):8749-56
14695190
Blood. 2010 Mar 25;115(12):2449-57
20097882
J Cell Mol Med. 2011 Sep;15(9):1857-64
21029368
Cancer Res. 1983 Jun;43(6):2704-11
6601984
Exp Hematol. 2007 Apr;35(4 Suppl 1):155-62
17379101
Matrix Biol. 2004 Oct;23(6):341-52
15533755
Clin Cancer Res. 2009 Feb 15;15(4):1210-21
19228727
FEBS J. 2010 Oct;277(19):3890-903
20840586
J Biol Chem. 2009 Sep 18;284(38):26085-95
19596856
Nat Med. 1998 Jun;4(6):691-7
9623978
Pathophysiol Haemost Thromb. 2008;36(3-4):195-203
19176992
Eur J Cancer. 2006 Jul;42(11):1581-90
16797965
Blood. 1987 Aug;70(2):551-7
2955820
Blood. 2007 Jun 1;109(11):4914-23
17339423
Br J Haematol. 2009 Jun;145(6):681-708
19344388
J Thromb Haemost. 2007 Apr;5(4):729-37
17408406
Leuk Lymphoma. 1999 Jan;32(3-4):249-56
10037022
Br J Haematol. 2002 Sep;118(3):817-20
12181051
Blood. 2000 Oct 1;96(7):2528-36
11001907
Biochemistry. 2002 Aug 20;41(33):10519-28
12173939
Stem Cells. 1995 Aug;13 Suppl 2:1-9
8520495
Blood. 1998 Feb 1;91(3):806-12
9446640
Invasion Metastasis. 1994-1995;14(1-6):290-302
7657522
J Exp Med. 2009 Mar 16;206(3):691-705
19255147
J Biol Chem. 2008 Nov 21;283(47):32628-36
18812315
Blood. 2002 Jul 15;100(2):610-7
12091355
Med Oncol. 2010 Jun;27 Suppl 1:S1-6
20169425
Blood. 1998 Oct 15;92(8):2908-13
9763577
Blood. 2010 Jan 21;115(3):601-4
19965677
Br J Haematol. 2005 Jan;128(2):210-7
15638855
Ann Oncol. 2010 Jun;21(6):1302-1307
19917571
J Biol Chem. 2007 May 4;282(18):13326-33
17347152
Br J Pharmacol. 2007 May;151(1):1-14
17339837
Blood. 2007 Sep 15;110(6):2041-8
17536013