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Identification and characterization of riproximin, a new type II ribosome-inactivating protein with antineoplastic activity from Ximenia americana

Cristina Voss^*, Ergül Eyol^*, Martin Frank, Claus-W. von der Lieth and Martin R. Berger^*,1

^* German Cancer Research Center, Toxicology and Chemotherapy Unit, E100, Heidelberg, Germany; and

German Cancer Research Center, Central Spectroscopic Department, B090, Heidelberg, Germany

¹Correspondence: Toxicology and Chemotherapy Unit, E100, Deutsches Krebsforschungszentrum Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. E-mail: m.berger{at}dkfz.de

ABSTRACT

The aim of this study was to identify and characterize the active component(s) of Ximenia americana plant material used to treat cancer in African traditional medicine. By a combination of preextraction, extraction, ion exchange and affinity chromatography, a mixture of two cytotoxic proteins was isolated. Using degenerated primers designed on the de novo sequence of two tryptic peptides from one of these proteins, a DNA fragment was amplified and the sequence obtained was used to determine the complete cDNA sequence by the RACE method. Sequence analysis and molecular modeling showed that the new protein, riproximin, belongs to the family of type II ribosome inactivating proteins. These results are in good agreement with the ability of riproximin to inhibit protein synthesis in a cell-free system, as well as with the cytotoxicity of riproximin, as demonstrated by its IC₅₀ value of 0.5 pM in MCF7, 1.1 pM in HELA and 0.6 pM in CC531-lacZ cells. To assess the antineoplastic efficacy of the purified riproximin in vivo, the CC531-lacZ colorectal cancer rat metastasis model was used. Significant anticancer activity was found after administration of total dosages of 100 (perorally) and 10 (intraperitoneally) pmol riproximin/kg. These results suggest that riproximin has distinct potential for cancer treatment. —Voss, C., Eyol, E., Frank, M., von der Lieth, C.-W., Berger, M. R. Identification and characterization of riproximin, a new type II ribosome-inactivating protein with antineoplastic activity from Ximenia americana.