An evolved ribosome-inactivating protein targets and kills human melanoma cells <it>in vitro </it>and <it>in vivo</it>

• Main Authors: Green David E, Kiarash Reza, Wei Xin, Perampalam Subodini, Revers Leigh, Cheung Melissa C, Abdul-Wahid Aws, Gariépy Jean
• Format: Article
• Language: English
• Published: BMC 2010-02-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/9/1/28

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>SLT-1A^IYSNKLMwas 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^IYSNKLMadministered intravenously into SCID mice bearing a human melanoma xenograft indicate that SLT-1A^IYSNKLMreadily accumulates at the tumor site as opposed to non-target tissues. Furthermore, the co-administration of SLT-1A^IYSNKLMwith DTIC resulted in tumor regression and greatly increased survival in this mouse xenograft model in comparison to DTIC or SLT-1A^IYSNKLMtreatment alone (115 day median survival versus 46 and 47 days respectively; <it>P </it>values < 0.001). SLT-1A^IYSNKLMis stable in serum and its intravenous administration resulted in modest immune responses following repeated injections in CD1 mice.</p> <p>Conclusions</p> <p>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^IYSNKLMcan specifically kill human melanoma cells <it>in vitro </it>and <it>in vivo</it>.</p>