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Oncogene. 2018 Apr;37(16):2181-2196. doi: 10.1038/s41388-017-0080-4. Epub 2018 Jan 31.

Clofarabine inhibits Ewing sarcoma growth through a novel molecular mechanism involving direct binding to CD99.

Author information

1
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
2
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy.
3
PROMETEO Laboratory, STB, RIT Department, Rizzoli Orthopaedic Institute, Bologna, Italy.
4
Department of Preventive Oncology, Cancer Institute, Hacettepe University, Ankara, Turkey.
5
Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
6
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy. katia.scotlandi@ior.it.
7
PROMETEO Laboratory, STB, RIT Department, Rizzoli Orthopaedic Institute, Bologna, Italy. katia.scotlandi@ior.it.
8
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA. au26@georgetown.edu.

Abstract

Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy that predominantly affects children and adolescents. CD99 is a cell surface protein that is highly expressed on ES cells and is required to maintain their malignancy. We screened small molecule libraries for binding to extracellular domain of recombinant CD99 and subsequent inhibition of ES cell growth. We identified two structurally similar FDA-approved compounds, clofarabine and cladribine that selectively inhibited the growth of ES cells in a panel of 14 ES vs. 28 non-ES cell lines. Both drugs inhibited CD99 dimerization and its interaction with downstream signaling components. A membrane-impermeable analog of clofarabine showed similar cytotoxicity in culture, suggesting that it can function through inhibiting CD99 independent of DNA metabolism. Both drugs drastically inhibited anchorage-independent growth of ES cells, but clofarabine was more effective in inhibiting growth of three different ES xenografts. Our findings provide a novel molecular mechanism for clofarabine that involves direct binding to a cell surface receptor CD99 and inhibiting its biological activities.

PMID:
29382926
DOI:
10.1038/s41388-017-0080-4
[Indexed for MEDLINE]

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