New anti-cancer agents through an interaction with tubulin

Microtubules (MTs) are involved in key cellular functions, such as cell division, cell motility and intracellular transport. Interfering with the MT dynamic equilibrium, by either inhibiting tubulin polymerization or blocking MT disassembly, has resulted in a productive strategy for the development of efficient anticancer agents. However, they can elicit drug resistance, toxicity and undesired side effects. Thus, new MT inhibitors would provide a better alternative to current anticancer treatments. New tubulin targeting heterocyclic compounds uniformly inhibit at nanomolar concentration the cancer cells including P-glycoprotein (Pgp) overexpressing lines NCI/ADR-RES and Messa/Dx5. Besides the inhibition of tubulin polymerization, the new agents stimulate the cytotoxic activity of natural killer cells at doses which do not severely affect cell viability, increasing NKG2D and DNAM-1 ligand up-regulation on HeLa cells. At higher concentrations, these compounds stably arrest mitotic progression, prevent mitotic slippage and the ensuing formation of aneuploid cells and induce cell death, with effectiveness comparable or superior to that obtained with VBL. Moreover such agents show strong inhibition of the Hedgehog signaling pathway and medulloblastoma D283 cells. 3-Aroyl-1,4-diarylpyrrole (ARDAP) derivatives exhibit potent inhibition of tubulin polymerization and inhibit the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. These results provide a robust scaffold to develop tubulin inhibitors with potential as novel treatments for CML.