Targeting Microtubules for Cancer Chemotherapy

Abstract

Chemical compounds that interfere with microtubules such as the vinca alkaloids and taxanes are important chemotherapeutic agents for the treatment of cancer. As our knowledge of microtubule-targeting drugs increases, we realize that the mechanism underlying the anti-cancer activity of these agents may mainly lie in their inhibitory effects on spindle microtubule dynamics, rather than in their effects on microtubule polymer mass. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, notably neurological and hematological toxicities. Drug resistance is another notorious factor that thwarts the effectiveness of these agents, as with many other cancer chemotherapeutics. Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to the existing microtubule-targeting drugs. Continued investigation of the mechanisms of action of microtubule-targeting drugs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance may provide more effective therapeutic options for cancer patients.

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

“…Microtubules form a mitotic spindle during cell division, which is the key machinery that drives the alignment of replicated chromosomes to the equatorial plane and mediates the subsequent segregation of chromosomes to the two daughter cells (Zhou and Giannakakou, 2005). The progression of mitosis is arrested until the spindle has been correctly assembled during the metaphase through a regulatory system called the spindle checkpoint system (Sampath and Plunkett, 2001).…”

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

“…The two 50-kDa subunits (α-and β-tubulin) are ∼50% identical to one another (2) and polymerize by nucleationelongation, in which noncovalent tubulin dimers are added at the ends of a short microtubule "nucleus" (3). In the polymerization stage, the tubulin heterodimers lay head to tail, with the α-subunit of one dimer in contact with the β-subunit of the next.…”

“…Microtubules exist in a dynamic state, growing and shortening by the reversible association and dissociation of α/β-tubulin heterodimers at both ends. The α-tubulin ringed (−) end is less dynamic, whereas the more dynamic β-tubulin ringed (+) end grows and shortens more rapidly (2).…”

Microtubule shuttles on kinesin-coated glass micro-wire tracks

“…Kinesin uses adenosine triphosphate (ATP) as a fuel and its 8 nm step size corresponds to the size of the tubulin pitch forming the microtubule (Vale and Milligan, 2000;Hwang and Lang 2009). Due to their physiological importance, pharmaceutical targeting of microtubules and kinesin is under intensive study for diseases such as Alzheimer's disease and cancer (Zhou and Giannakakou, 2005;Craddock et al, 2012;Rath and Kozielski, 2012). Moreover, by virtue of in-vitro formation of microtubules (Weisenberg, 1972) and successful reconstruction of the kinesin/microtubule-based motility , this bio-motile system has been utilized as a model system for the study of pattern formation driven by motor proteins (Nedelec, 1997;Schaller et al, 2010;Sumino et al, 2012).…”