An evolved ribosome-inactivating protein targets and kills human melanoma cells in vitro and in vivo.

Molecular Cancer
Melissa C CheungJean Gariépy

Abstract

Few treatment options exist for patients with metastatic melanoma, resulting in poor prognosis. One standard treatment, dacarbazine (DTIC), shows low response rates ranging from 15 to 25 percent with an 8-month median survival time. The development of targeted therapeutics with novel mechanisms of action may improve patient outcome. Ribosome-inactivating proteins (RIPs) such as Shiga-like Toxin 1 (SLT-1) represent powerful scaffolds for developing selective anticancer agents. Here we report the discovery and properties of a single chain ribosome-inactivating protein (scRIP) derived from the cytotoxic A subunit of SLT-1 (SLT-1A), harboring the 7-amino acid peptide insertion IYSNKLM (termed SLT-1A IYSNKLM) allowing the toxin variant to selectively target and kill human melanoma cells. SLT-1A IYSNKLM was able to kill 7 of 8 human melanoma cell lines. This scRIP binds to 518-A2 human melanoma cells with a dissociation constant of 18 nM, resulting in the blockage of protein synthesis and apoptosis in such cells. Biodistribution and imaging studies of radiolabeled SLT-1A IYSNKLM administered intravenously into SCID mice bearing a human melanoma xenograft indicate that SLT-1AI YSNKLM readily accumulates at the tumor site as opposed to...Continue Reading

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Citations

Jun 20, 2012·Journal of Hematology & Oncology·Niraj ShenoyAmit Verma
Apr 10, 2012·Bioscience, Biotechnology, and Biochemistry·Ali Jahanian-NajafabadiLorenz M Mayr
Jun 17, 2011·PloS One·Alexey V StepanovSergey M Deyev
Sep 11, 2012·Toxicon : Official Journal of the International Society on Toxinology·Jonas BerganKirsten Sandvig
Dec 20, 2018·Epigenomics·Katerina GrafanakiConstantinos Stathopoulos

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Methods Mentioned

BETA
RIP
ELISA
xenografts
phage display
PCR

Software Mentioned

RESCRIPT
GraphPad
GraphPad Prism

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