Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option?

Abstract

Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.

Figure 1

The dynamic nature of cytoskeleton is due to cycles of microtubule catastrophes. (a) Model structure of assembled cytoskeleton. The variety of shapes and sizes of the microtubule cytoskeleton is as great as the number of different cell types. In interphase, microtubules are long and stable because there are almost no catastrophes. (b) In mitosis, catastrophes are relatively frequent, resulting in highly dynamic microtubules that reach a steady-state length after a few minutes of growth (c). (d) After the segregation of chromatids, a new cycle of depolymerization and polymerization begins, resulting in a new stable microtubule cytoskeleton in daughter's cells (d). Blue and red arrows indicate effects of stabilizing and destabilizing agents, all resulting in cell cycle arrest.

Figure 2

Mechanism of action of cryptophycins.

Figure 3

Classification of cryptophycins.

Figure 4

Combretastatin A-4-P: mechanisms of action at tumor level.

Figure 5

Similarities and differences between mechanisms of action and activity of microtubule-stabilizing agents.