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

作者：Cheung Melissa C; Revers Leigh; Perampalam Subodini; Wei Xin; Kiarash Reza; Green David E; Abdul Wahid Aws; Gariepy Jean^*

来源：Molecular Cancer, 2010, 9: 28.

DOI：10.1186/1476-4598-9-28

Background: 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.
Results: 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-1A(IYSNKLM) readily accumulates at the tumor site as opposed to non-target tissues. Furthermore, the co-administration of SLT-1A(IYSNKLM) with DTIC resulted in tumor regression and greatly increased survival in this mouse xenograft model in comparison to DTIC or SLT-1A(IYSNKLM) treatment alone (115 day median survival versus 46 and 47 days respectively; P values < 0.001). SLT-1A(IYSNKLM) is stable in serum and its intravenous administration resulted in modest immune responses following repeated injections in CD1 mice.
Conclusions: These results demonstrate that the evolution of a scRIP template can lead to the discovery of novel cancer cell-targeted compounds and in the case of SLT-1A(IYSNKLM) can specifically kill human melanoma cells in vitro and in vivo.

• 出版日期2010-2-3