Claudia Maletzki, Ulrike Klier, Samuel Marinkovic, Ernst Klar, Jörg Andrä, Michael Linnebacher
Host defense peptides (HDP) constitute effector molecules of the innate immune system. Besides acting against microbia and fungi, they exhibit broad and selective oncolytic activity. The underlying mechanism is at least partially attributable to elevated surface-exposed levels of phosphatidylserine (PS) on tumor targets. In this study, comprehensive analysis of NK-2-based derivatives (C7A, C7A-D21K, and C7A-Δ) was done on patient-derived ultra-low passage colorectal carcinoma (CRC) cell lines. Peptides were designed to improve antitumoral potential. Mellitin was used as positive control and a non-toxic peptide (NK11) served as negative control. Subsequently, effectiveness of local HDP application was determined in xenopatients. Generally, CRC lines displayed a heterogeneous pattern of surface-exposed PS, which was usually below standard CRC cells. Of note, five out of seven cell lines were susceptible towards HDP-mediated lysis (lytic activity of peptides: C7A-D21K > C7A-Δ= C7A). Oncolytic activity correlated mostly with surface-exposed PS levels. Apoptosis as well as necrosis were involved in killing. In an in vivo experiment, substantial growth inhibition of HROC24 xenografts was observed after HDP therapy and, surprisingly, also after NK11 treatment. These promising data underline the high potential of HDPs for oncolytic therapies and may provide a rationale for optimizing preclinical treatment schedules based on NK-2.
Future Oncol. 2012 Aug;8(8):999-1014
[PMID:
22894672]
Proc Natl Acad Sci U S A. 1991 May 1;88(9):3792-6
[PMID:
1708887]
PLoS One. 2012;7(12):e52485
[PMID:
23300683]
Int J Mol Sci. 2011;12(11):8027-51
[PMID:
22174648]
PLoS One. 2011 Mar 31;6(3):e18321
[PMID:
21483840]
Carcinogenesis. 2010 Jan;31(1):100-10
[PMID:
19934210]
Exp Cell Res. 2013 Apr 15;319(7):1013-27
[PMID:
23298945]
FEBS Lett. 2005 Nov 7;579(27):6128-34
[PMID:
16269280]
Int J Mol Sci. 2009 Sep 09;10(9):3951-70
[PMID:
19865528]
J Pept Sci. 2013 Oct;19(10):619-28
[PMID:
23893605]
Peptides. 2009 Apr;30(4):660-8
[PMID:
19154767]
Nature. 2002 Jan 24;415(6870):389-95
[PMID:
11807545]
Cancer Res. 2009 Apr 15;69(8):3458-63
[PMID:
19351852]
BMC Cancer. 2010 Jul 08;10:362
[PMID:
20615215]
Blood. 1997 Feb 15;89(4):1121-32
[PMID:
9028933]
Int J Oncol. 2009 Aug;35(2):321-7
[PMID:
19578746]
J Membr Biol. 1997 Apr 1;156(3):197-211
[PMID:
9096062]
Biochim Biophys Acta. 2003 Jun 10;1612(2):164-71
[PMID:
12787934]
J Cancer. 2012;3:196-206
[PMID:
22606209]
Antimicrob Agents Chemother. 2004 May;48(5):1593-9
[PMID:
15105110]
J Bioenerg Biomembr. 2011 Jun;43(3):275-85
[PMID:
21643697]
Cancer Res. 2002 Nov 1;62(21):6132-40
[PMID:
12414638]
Anticancer Res. 2002 Sep-Oct;22(5):2703-10
[PMID:
12529985]
Cancer Res. 1991 Jun 1;51(11):3062-6
[PMID:
2032247]
Int J Cancer. 2011 Jun 15;128(12):2994-3004
[PMID:
20734391]
Biochem J. 1999 Aug 1;341 ( Pt 3):501-13
[PMID:
10417311]
Biochim Biophys Acta. 1999 Dec 15;1462(1-2):55-70
[PMID:
10590302]
Biol Chem. 2012 Aug;393(8):817-27
[PMID:
22944683]
Cell Immunol. 1998 Nov 1;189(2):107-15
[PMID:
9790724]
Surg Oncol. 2007 Dec;16 Suppl 1:S7-9
[PMID:
18023574]
Peptides. 2010 Aug;31(8):1504-10
[PMID:
20493915]
Cancer Res. 2006 May 15;66(10):5371-8
[PMID:
16707464]
