The development of new anticancer drugs is a salient problem and the traditional use of plants is a potentially rich source of information for detecting new molecules with
antineoplastic activity. Riproximin is a recently detected cytotoxic type II
ribosome inactivating protein with high selectivity for certain tumor cell lines. Its activity was recognized as the main component in a plant
powder used by African healers for treating
cancer. By
ribulose bisphosphate carboxylase gene sequencing analysis, the
powder was identified to be derived from the plant Ximenia americana. The
cDNA sequence of riproximin was identified, the
protein was modeled to contain one A- and a B-chain, respectively, and a reliable purification procedure from kernels of X. americana was established. Riproximin displays high but differential antiproliferative activity in a panel of human and rodent
cancer cell lines, with concentrations inhibiting cell proliferation by 50% (IC50 values) that diverge by
a factor of 100. Consistent
antineoplastic activity was detected in colorectal and
pancreatic cancer liver
metastasis models in rats. The cytotoxic mechanism of action was determined to be based on cellular uptake of riproximin followed by its A-chain prompted depurination of the
28S ribosomal RNA and induction of unfolded protein response. Riproximin's specificity depended on its B-chain connected binding to cell surface
glycans, the presence of which is crucial for subsequent internalization into cells and cytotoxicity. These N- and O-
glycans include bi- and tri-antennary NA structures (NA2/NA3) as well as Tn3 structures (clustered
Tn antigen). Riproximin was found to crosslink
proteins with N- and O-
glycan structure, thus indicating both types of binding sites on its B chain. Due to this crosslinking ability, riproximin is expected to show prominent cytotoxicity towards cells expressing both, NA2/NA3 and clustered Tn structures. Apart from the properties of riproximin, the plant X. americana has been known for some medical uses in
traditional African medicine, including various types of
infections.