Cell division and the equitable segregation of chromosomes into the two daughter cells depend on an elaborate cell apparatus, the mitotic spindle. This spindle is basically formed of a bundle of tubular fibres called microtubules. This core role in cell division played by the microtubules has made them the target of several anticancer agents widely used in chemotherapy treatments, such as Taxotere^® and Navelbine^®.

The basic building block of microtubules is tubulin. Tubulin can be cyclically modified by deleting then re-adding its last C-terminal amino acid, which is a tyrosine. It is the specific enzymes tubulin-tyrosine ligase (TTL) and tubulin carboxypeptidase (TCP) that operate this cyclical modification, which produces two forms of tubulin, tyrosinated tubulin and detyrosinated tubulin. The pioneering research led by the team ^[1] and later confirmed by other laboratories ^[2] has demonstrated that this tyrosination/detyrosination cycle plays a major role in the progression and severity of human cancers. What happens during tumour growth is that the cancer cells eliminate TTL ^[3] and accumulate abnormally high amounts of detyrosinated tubulin. This abnormal accumulation is related to poor-prognosis cancers ^[1].

Studies conducted on yeast and on TTL-null mice have provided a molecular explanation for this effect. They have revealed that an absence of the C-terminal tyrosine affects the binding of particular proteins (Cap-Gly domain proteins), which in turn disturbs the correct positioning of the mitotic spindle, thus fostering tumour progression ^{[4, 5]}. 

By preventing the abnormal tumour accumulation of detyrosinated tubulin, TCP inhibitors may become a new class of anti-cancer agents. However, it has so far proved impossible to purify the enzyme, which is a major stumbling block in the drive to identify specific inhibitors. The team at CMBA: Center for the screening for BioActive Molecules, developed a cellular TCP activity test which they then deployed via high-throughput screening to search for the inhibitors in a library of around 25,000 extracts of natural substances, with help from Pierre Fabre laboratories. This resulted in the selection of two inhibitor molecules classed as sesquiterpenic lactones. Working in partnership with the iBITec-S high-throughput screening and combinatorial chemistry research group (G3C), the teams went on to show that parthenolide, a structural analogue of these lactones, is an efficient inhibitor of cellular TCP activity. Parthenolide is a molecule best known as an anti-migraine, since it possesses NFκB pathway inhibitor properties. The researchers conducting the study have also shown that the parthenolide’s TCP-inhibitor activity was independent of its action on NFkappaB pathway.

This new, specific action of parthenolide may hold the key to its other anti-cancer and anti-metastatic properties, which remain largely arcane. The net result is that parthenolide, which has already successfully passed phase I clinical trials, may well be a promising new multifunctional anti-cancer drug ^[6].