Three teams of the CNRS have studied a small molecule that can greatly reduce the growth of tumors and their vasculature. Its effects seem fairly well understood and that agent shows no toxicity to healthy tissue. Moreover, its synthesis on an industrial scale is easy. Clinical trials should begin next year.
This molecule is called for now HB-19, but it could be known by the name of Nucant, the name chosen by the company ImmuPharma, which will begin clinical trials in 2009. Chemically, it is a small peptide amended (known as pseudopeptide), ie a molecule of the same family as proteins and thus composed of amino acids. In 1998, she had been synthesized by the team of Ara Hovanessian to become an inhibitor of entry into cells of HIV (the virus that causes AIDS).
HB-19 binds selectively to a particular protein, nucléoline. It owes its name from its presence in the nucleus, where it knows that it is involved in the metabolism of DNA and RNA. It is also found in the rest of the cell (cytoplasm). There she plays carriers. It binds easily to different proteins, that accompanies the kernel. It also clings to the mRNA (messenger RNA), these pieces of genetic codes used to produce proteins, and appears to play an active role in controlling their expression. Finally, she moved to the cell surface, where it can accommodate all kinds of molecules, for example setting of growth factors or viruses. In short, nucléoline is a molecule with multiple roles. It knows that it is particularly active in tumor cells and the endothelial cells that produce new blood vessels, including around a tumor.
To study the effects of HB-19 on nucléoline, three teams are involved: that of Ara Hovanessian (Laboratory regulation of transcription and genetic diseases, University of Paris Descartes / CNRS), Jean-Paul Briand (Immunology Laboratory and chemistry therapeutic , ICT / CNRS) and Jose Courty (Laboratory research on cell growth, repair and regeneration of tissue).
We know that HB-19 binds the hard way nucléoline which lies on the cell membrane. Thus riding, the protein is leaving his post and enters the cytoplasm where it is destroyed. To test the effects, researchers have used different cultures of tumor cells. Their work, which has just been published in the journal PlosOne demonstrates that HB-19 prevents the proliferation of cells of different tumors (including melanoma, breast cancer, colon or prostate). This small peptide also inhibits the formation of blood vessels (so-called angiogenesis) around the tumor. The action on the regression of tumors has been verified in vivo in an animal model (mice that received human tumor cells).
The images left (C) show HB-19 (red) immediately after the addition of this molecule (top) and after one hour of incubation (bottom). HB-19 sets immediately to the nucléoline of the membrane (HB-19 binding) and is therefore around the cell. In those below (HB-19 Entry), the molecule was widely distributed within the cell, where it will be destroyed, without entering into the nucleus (blue). The images show the right nucléoline kernel (coloured green). With HB-19 (bottom), the quantities observed are the same as in the absence of this molecule (top), evidence that HB-19 only affects the nucléoline of the membrane. (Image taken from the publication) © PlosOne
A good candidate for a future drug
Of the cultured cells, researchers have observed the spread of HB-19 molecule linked to the nucléoline. It is clear that only the proteins present on the membrane of cells are destroyed. The nucléoline kernel is not affected, which is a good point for use as a medicinal product. HB-19 would affect less normal cells, with many nucléoline in the nucleus but little on their membrane. The lack of toxicity of HB-19 has been demonstrated.
Moreover, its good solubility and its structure make this molecule to manufacture and easy to administer. All criteria of a potentially effective anticancer drugs are combined. It now remains to verify that these promises are actually held in humans. That attempt to ImmuPharma with his Nucant directly derived from HB-19, in clinical trials to start next year. The company hopes that its Nucant same could also be used against psoriasis and diabetic retinopathy of origin and even for the healing of wounds.
