Cell constituents called microtubules made up of α- and β-tubulin dimerized subunits form hollow, cylindrical, filamentous structures. They play a major role in cell machinery, manage cell growth and division, cell motility, preserve cell shape and regulate intracellular trafficking. Tubulin is the primary target of a growing number of natural, semisynthetic and synthetic products developed as potential anticancer agents with varied mechanisms of action and limitations such as the development of multidrug resistance and cytotoxicity.
Recently, Sapienza University of Rome scientists: Dr. Giuseppe La Regina, Dr. Antonio Coluccia, Dr. Valentina Naccarato and Professor Romano Silvestri compiled and critically reviewed the literature on a list of potential molecules that disrupt cell division as a result of binding to α,β-dimers, oligomers, or polymers. This work was published in the peer-reviewed journal, European Journal of Pharmaceutical Sciences.
The authors provided their expert opinion for twenty six (26) antimitotic agents which included natural, synthetic and semisynthetic products with different chemical structures which do not interact with tubulin in the same binding site. To facilitate the understanding of the researchers, the Italian team grouped them into (i) inhibitors of microtubule assembly which either bind in the CLC site, or bind in the Vinca domain, or alkylate tubulin sulfhydryl groups; (ii) stabilizers of microtubules which bind with high affinity to polymerized tubulin versus α, β-tubulin heterodimer.
Examples of inhibitors of microtubule assembly that the researchers reviewed include colchicine site compounds which bind in a site on tubulin located at the interface between the α- and β-subunits; Combretastatin family which are naturally occurring and showed potent anticancer activity; 3-Formyl-2-phenylindoles a synthetic agent that inhibited tubulin polymerization and showed cytostatic effect; 2,3-Diarylindoles, a synthetic product with strong activity ; D-24851 the most effective of a series of indol-3-yl-2-oxoacetamides with in vitro and in vivo antitumor activity; Arylthioindoles as tubulin polymerization and MCF-7 cell growth inhibitors; 3-Aroyl-1-arylpyrroles and 3-aroyl-1,4-diarylpyrroles, a product of indole splitting of benzofused ring strategy; 2-Methoxyestradiol with potent activity in a variety of cancer types; Nocodazole with a weak affinity for βIII tubulin and DJ101, stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multiple drug resistance of existing tubulin inhibitors.
Vinca alkaloids agents including Vincristine and vinblastine as well as Vinflunine with a better safety profile than other vinca alkaloids, because it induces a smaller degree of neuropathy; Tryprostatins A and B interferes with tubulin assembly and M-phase of cell cycle; Moroidin inhibited the tubulin polymerization with an IC50 of 3.0 μM, a concentration that was lower than that of cochicine (IC50 = 10 μM).; Hemiasterlin which inhibits tubulin assembly, prevents the binding of vinblastine to tubulin; Diazonamide A, a marine natural product and B which were found to be less active.
Agents with stabilization of microtubules as their mechanism of action described in the paper include taxanes such as paclitaxel and docetaxel which have poor water solubility, difficult oral administration and multidrug resistance; Ortataxel and BMS-275183 which were synthesized to improve lipophilicity and pharmacokinetic properties of paclitaxel and cabazitaxel. They are used in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer; Epothilones such as Epothilones A-D which activity against paclitaxel-resistant cancer cells and have better water solubility; Ixabepilone with an antiangiogenetic activity superior to paclitaxel; BMS-310705 and sagopilone which have antitumor activity against several preclinical tumor models, including tumors resistant to most used anticancer drugs and can cross the blood-brain barrier. Laulimalide was found to have an extremely potent inhibition of solid tumor cell lines.
The comprehensive review will be of great importance to researchers interested in developing anticancer agents with mechanism involving tubulin interaction. Moreover, professor Romano Silvestri and his colleagues postulated that microtubule targeting anticancer agents which circumvent the risk of drug resistance may improve the tolerability and optimize drug combination and therapies. They also concluded that the ability of Microtubule targeted agents to have a multi target mechanism of action might form the basis for the creation of personalized anticancer agents.
Giuseppe La Regina, Antonio Coluccia, Valentina Naccarato, Romano Silvestri. Towards modern anticancer agents that interact with tubulin. European Journal of Pharmaceutical Sciences 131 (2019) 58 -68Go To European Journal of Pharmaceutical Sciences