CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice.

Dysfunction of the NF1 gene coding a RAS GAP is the major cause of neurofibromatosis type 1 (NF1), whereas neurofibromatosis type 2 (NF2) is caused primarily by dysfunction of the NF2 gene product called merlin that inhibits directly PAK1, an oncogenic Rac/CDC42-dependent Ser/Thr kinase. It was demonstrated previously that PAK1 is essential for the growth of both NF1 and NF2 tumors. Thus, several anti-PAK1 drugs, including FK228 and CEP-1347, are being developed for the treatment of NF tumors. However, so far no effective NF therapeutic is available on the market. Since propolis, a very safe healthcare product from bee hives, contains anticancer ingredients called CAPE (caffeic acid phenethyl ester) or ARC (artepillin C), depending on the source, both of which block the oncogenic PAK1 signaling pathways, its potential therapeutic effect on NF tumors was explored in vivo. Here it is demonstrated that Bio 30, a CAPE-rich water-miscible extract of New Zealand (NZ) propolis suppressed completely the growth of a human NF1 cancer called MPNST (malignant peripheral nerve sheath tumor) and caused an almost complete regression of human NF2 tumor (Schwannoma), both grafted in nude mice. Although CAPE alone has never been used clinically, due to its poor bioavailability/water-solubility, Bio 30 contains plenty of lipids which solubilize CAPE, and also includes several other anticancer ingredients that seem to act synergistically with CAPE. Thus, it would be worth testing clinically to see if Bio 30 and other CAPE-rich propolis are useful for the treatment of NF patients.

Midkine (MK), a retinoic acid (RA)-inducible gene product, produced in E. coli acts on neuronal and HL60 leukemia cells.

We have shown previously that (i) retinoic acid (RA), an anti-neoplastic agent, activates the midkine (MK) gene in mammalian embryonic carcinoma cells, and that (ii) the MK of 118 amino acids, purified from L cells, induces neurite outgrowth of mammalian embryonic brain cells. In this paper, we describe an unconventional strategy for the purification of a fully active MK from E. coli with a high yield. The MK was overproduced in E. coli as a glutathione S-transferase (GST) fusion protein. The MK fusion protein extracted from the bacterial inclusion bodies with guanidine-HCl was renatured, refolded slowly and cleaved by thrombin at the site where the GST links to the MK. The purified free MK, like RA, induced neurite outgrowth from central neurons of the mouse spinal cord, and suppressed the growth of human HL60 leukemia cells in vitro. Unlike RA, however, the MK did not induce granulocytic differentiation of HL60 cells. Furthermore, the MK supported the survival of an NGF-insensitive sensory neuron subpopulation(s) from chicken embryo dorsal root ganglion. Thus, the actions of the MK and leukemia inhibitory factor (LIF) are surprisingly similar. There is no sequence similarity between MK and LIF, however, and unlike MK, LIF production does not appear to be RA-inducible.