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.

A regulatory subunit of protein phosphatase 2A, PPP2R5E, regulates the abundance of microtubule crosslinking factor 1

“…We showed that PPP2R5E is required for the stabilization of MTCL1. Disruption of MT organization is associated with a loss of cell polarity and a defect in cell division, which are often observed in malignant cancer cells . Our results suggest the possibility that MT organization induced by the stabilization of MTCL1 may be one of the mechanisms for PPP2R5E‐mediated tumor suppression.…”

Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma

“…On the other hand, microtubule-destabilizing agents suppress tubulin polymerization and can be further characterized into two groups: vinca-domain binders and colchicine-domain binders. Although the wide application of microtubule inhibitors is observed, there is urgent need to overcome several emerging challenges including drug-resistance and neurotoxicity [24,25]. …”

Human MAP tau based targeted cytolytic fusion proteins

“…Most microtubule targeting drugs (stabilizing or destabilizing) exploit this delicate moment of mitotic cell division to exert their cytotoxic activity, often by the common mechanism of suppressing microtubule dynamics and the chronic activation of spindle assembly checkpoint-SAC which halts cell-division in a prolong event that signals the induction of apoptosis (figure 1) [9]. Anti-mitotics like the vinca alkaloids (vinflunine, vincristine, vinorelbine, vindesine and eribulin), cryptophycins, halichondrins, estramustine, colchicines, and combretastatins are examples of drugs known to depolymerize / destabilize microtubules by binding to various β-tubulin sites [5,10,11]. On the other hand, taxanes paclitaxel (Taxol), Laulimalide, Dictyostatin, the epothilones, etc.…”