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J Cell Mol Med. 2018 Dec;22(12):5978-5990. doi: 10.1111/jcmm.13870. Epub 2018 Oct 24.

Targeting c-met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma.

Author information

1
Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, China.
2
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
3
Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China.
4
Nursing Department, Xiangya Hospital, Central South University, Changsha, China.
5
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Hepatocyte growth factor (HGF)/c-met pathway activation has been implicated in the pathogenesis of multiple myeloma (MM), and blocking this pathway has been considered a rational therapeutic strategy for treating MM. Aptamers are single-stranded nucleic acid molecules that fold into complex 3D structures and bind to a variety of targets. Recently, it was reported that DNA aptamer SL1 exhibited high specificity and affinity for c-met and inhibited HGF/c-met signaling in SNU-5 cells. However, as the first c-met-targeted DNA aptamer to be identified, application of SL1 to myeloma treatment requires further investigation. Here, we explore the potential application of SL1 in MM. Our results indicated that c-met expression is gradually increased in MM patients and contributes to poor outcomes. SL1 selectively bound to c-met-positive MM cells but not to normal B cells and suppressed the growth, migration and adhesion of MM cells in vitro in a co-culture model performed with HS5 cells, wherein SL1 inhibited HGF-induced activation of c-met signaling. In vivo and ex vivo fluorescence imaging showed that SL1 accumulated in the c-met positive tumour areas. In addition, SL1 was active against CD138+ primary MM cells and displayed a synergistic inhibition effect with bortezomib. Collectively, our data suggested that SL1 could be beneficial as a c-met targeted antagonist in MM.

KEYWORDS:

CLN0003_SL1; aptamer; bortezomib; c-met receptor; multiple myeloma

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