TRAIL and doxorubicin combination induces proapoptotic and antiangiogenic effects in soft tissue sarcoma in vivo.
OBJECTIVE
Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xenografts in vivo.


METHODS
TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes.


RESULTS
TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P < 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro.


CONCLUSIONS
Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted.
Wang
Suizhao
S
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ren
Wenhong
W
Liu
Jeffery
J
Lahat
Guy
G
Torres
Keila
K
Lopez
Gonzalo
G
Lazar
Alexander J
AJ
Hayes-Jordan
Andrea
A
Liu
Kebin
K
Bankson
Jim
J
Hazle
John D
JD
Lev
Dina
D
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D054357:Chemokine CXCL10; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin
Blood. 2001 Aug 1;98(3):795-804
11468181
Clin Cancer Res. 2009 Mar 15;15(6):2039-47
19276256
Nature. 1997 Apr 3;386(6624):517-21
9087414
Circ Res. 2003 Apr 18;92(7):732-40
12649264
J Clin Oncol. 2009 Jul 1;27(19):3126-32
19451427
Lancet Oncol. 2000 Oct;1:75-85
11905672
Cochrane Database Syst Rev. 2003;(3):CD003293
12917960
Br J Cancer. 2003 Jan 27;88(2):298-306
12610517
Prostate. 2005 Feb 1;62(2):165-86
15389801
Cancer Res. 2009 Feb 1;69(3):1080-8
19155307
Curr Cancer Drug Targets. 2008 Sep;8(6):536-44
18781899
J Orthop Res. 2003 Sep;21(5):949-57
12919886
J Immunol. 2007 Jan 15;178(2):1122-35
17202376
Clin Cancer Res. 2008 Sep 1;14(17):5466-75
18765538
Carcinogenesis. 2006 Sep;27(9):1768-77
16571651
Ann Surg Oncol. 1998 Jan-Feb;5(1):48-53
9524708
J Clin Oncol. 2007 Apr 10;25(11):1390-5
17416859
J Clin Oncol. 2008 Dec 1;26(34):5583-8
18981463
J Clin Oncol. 2004 Nov 15;22(22):4567-74
15542808
Int J Oncol. 2002 May;20(5):949-54
11956588
Eur J Cancer. 2003 Jun;39(9):1318-29
12763223
J Immunol. 2003 Mar 15;170(6):3369-76
12626597
J Clin Invest. 1999 Jul;104(2):155-62
10411544
Nat Rev Cancer. 2005 Nov;5(11):876-85
16239906
Cancer Res. 2001 Mar 15;61(6):2704-12
11289151
Cancer Lett. 2002 Apr 25;178(2):167-74
11867201
Cancer. 2001 Sep 15;92(6):1556-66
11745235
Int J Oncol. 2004 Sep;25(3):677-84
15289869
Cancer. 1999 Jan 15;85(2):389-95
10023707
Nat Rev Cancer. 2008 Oct;8(10):782-98
18813321
Cancer Res. 2008 May 1;68(9):3440-9
18451172
Clin Cancer Res. 2007 Oct 15;13(20):6187-94
17947486
J Orthop Surg (Hong Kong). 2001 Dec;9(2):19-22
12118126
Int J Oncol. 2004 May;24(5):1263-70
15067350
Int J Cancer. 2003 Dec 20;107(6):929-40
14601052
Int J Oncol. 2006 Jan;28(1):127-33
16327988
Mol Cancer Ther. 2006 Dec;5(12):2977-90
17172403
Ann N Y Acad Sci. 2003 Dec;1010:195-9
15033719
Mol Cell. 1999 Oct;4(4):563-71
10549288
Clin Cancer Res. 2003 May;9(5):1648-55
12738717
Neoplasia. 2004 Jul-Aug;6(4):364-73
15256058
N Engl J Med. 2005 Aug 18;353(7):701-11
16107623
Int J Cancer. 2002 Jun 1;99(4):491-504
11992538
Br J Cancer. 2006 May 22;94(10):1428-35
16622457
Am J Physiol Lung Cell Mol Physiol. 2000 May;278(5):L1045-50
10781437
Neoplasia. 2001 Nov-Dec;3(6):535-46
11774036
Clin Cancer Res. 2009 May 15;15(10):3472-83
19417021