No abstract

Recently, new chemotherapy agents which target the non-structural components of mitosis have been developed. An important protein involved in several mitotic phases is the Aurora-A protein. By means of the phosphorylation of different substrates, Aurora-A regulates the correct development of the various phases of mitosis. The kinase activity of this protein makes Aurora-A an excellent candidate as an oncogene. The first data of Aurora-A involvement in cancer regarded the identification of Aurora-A overexpression in primary breast and colon tumour samples. With regard to the predictive role of Aurora-A, it has been shown that its overexpression disrupts the spindle checkpoint activated by paclitaxel (Taxol) or nocodazole treatment, thus inducing the cells to become resistant to these drugs. The development therefore of small molecules with an Aurora-A inhibition function may make it possible to reduce or block the oncogenic activity of Aurora-A and in addition may improve the survival of oncological patients showing resistance to paclitaxel or nocodazole treatment. Three novel Aurora kinase inhibitors have recently been described--Hesperadin, ZM447439 and VX-680. All these three drugs have been designed to target the ATP-binding site of Aurora kinase, so they inhibit all three Aurora kinase family members showing a similar phenotype when tested in cell-based assays. Among these three different molecules, VX-680 has shown promising results in in vitro and in vivo studies. In conclusion, it is clear that we are entering a new era in anti-mitotic therapy with the identification and now clinical translation of new targets in mitosis beyond tubulin but many questions remain with regard to Aurora function.

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with high mortality. One of the MYC family genes, MYC, MYCL or MYCN, is amplified in ~20% of the SCLCs; therefore, MYC proteins are potential therapeutic targets in SCLC patients. We investigated the therapeutic impact of Omomyc, a MYC dominant negative, in a panel of SCLC cell lines. Strikingly, Omomyc suppressed the growth of all tested cell lines by inducing cell cycle arrest and/or apoptosis. Induction of G1 arrest by Omomyc was found to be dependent on the activation of CDKN1A, in part, through the TP73 pathway. Our results strongly indicate that SCLC cells carrying amplification of MYC, MYCL or MYCN are addicted to MYC function, suggesting that MYC targeting would be an efficient therapeutic option for SCLC patients.

CTCF is an evolutionary conserved and ubiquitously expressed protein that binds thousands of sites in the human genome. Ectopic expression of CTCF in various normal and tumoral human cell lines inhibits cell division and clonogenicity, with the consequence to consider CTCF a potential tumor-suppressor factor. In this review article, we focused on the molecular mechanisms engaged by CTCF to modulate the expression of several key-regulators of differentiation, cellular senescence, cell cycle control and progression, whose expression is frequently altered in tumors. Moreover, we discussed common features of CTCF at each tumor-related DNA-binding sequence, such as protein-partners, post-translational modifications, and distinctive epigenetic marks establishment. The investigation of the molecular mechanisms engaged by CTCF to modulate tumor-related genes emphasizes the cell-type dependency of its tumor suppressor role. Indeed, the ability of CTCF to bind their promoters strictly depends by cell-type features as DNA methylation, BORIS-binding and post-translational modifications as PARYlation.