Abstract
Simple SummaryMicrotubules (MTs) are highly conserved proteins present in all eukaryotic organisms. They form the cell cytoskeleton, and its function is essential for a large number of biological processes. Drugs against MTs (i.e., microtubule-targeting agents or MTAs) have been used for centuries to treat arthritis and gout. In the last 100 years, new MTAs either isolated from natural sources or synthesized in labs have been used to treat a great variety of human illnesses, from cancer and neurodegenerative diseases to the elimination of parasites. In this review, we analyze how MTAs bind to MTs, and the molecular mechanisms behind MTAs function, and we describe the last and novel roles of these drugs.Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment. They interfere with microtubule (MT) dynamics by either stabilizing or destabilizing MTs, and in culture, they are believed to kill cells via apoptosis after eliciting mitotic arrest, among other mechanisms. This classical view of MTA therapies persisted for many years. However, the limited success of drugs specifically targeting mitotic proteins, and the slow growing rate of most human tumors forces a reevaluation of the mechanism of action of MTAs. Studies from the last decade suggest that the killing efficiency of MTAs arises from a combination of interphase and mitotic effects. Moreover, MTs have also been implicated in other therapeutically relevant activities, such as decreasing angiogenesis, blocking cell migration, reducing metastasis, and activating innate immunity to promote proinflammatory responses. Two key problems associated with MTA therapy are acquired drug resistance and systemic toxicity. Accordingly, novel and effective MTAs are being designed with an eye toward reducing toxicity without compromising efficacy or promoting resistance. Here, we will review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs.
Highlights
Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment
MTAs like the taxanes downregulate the expression of Angiopoietin-1 (Ang-1), a protein required for vascular development and angiogenesis [200], and upregulate the expression and increased secretion of Thrombospondin 1 in the tumor microenvironment, a protein that is able to inhibit the formation of new blood vessels [201,202]
A housekeeping protein, as MTs participate in a wide variety of essential cellular activities including but not limited to cell division
Summary
Microtubules (MTs) are hollow cylindrical polymers composed of tubulin dimers. They play vital roles in a wide variety of cellular functions: intracellular trafficking, cell shape and morphology, positioning of organelles inside the cell, cell motility and migration, and the assembly of the mitotic spindle, which is the machinery responsible for chromosome segregation during mitosis [1] (Figure 1). Α andGTP, β tubulins assemble to form is hetin all eukaryotic studied thusThe far.widely Both distributed of them bind but only β tubulin able erodimers that will constitute the cytoplasmic microtubules, and they have to hydrolyze GTP during microtubule polymerization. G tubulin is part of the machinery been found in all eukaryotic cells studied far Both of them bind GTP, but only β that nucleates microtubule growth.GTP δ, during ε, andmicrotubule ζ tubulinspolymerization. MTs present with a polarity consisting of a plus-end where tubulin dimers are preferentially added, and a minus-end often embedded within the centrosome, the 3chief of 22 microtubule organizing center (MTOC) of most human cells. An virtually all MT-dependent biological ample cohort of microtubule-associated proteins like the end-binding proteins EB1, EB2, and EB3 regulate this process
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