Microtubule dynamics, suppression

Ixabepilone (38 Ixempra, BMS-247550 Bristol-Myers Squibb, 2007), a semi-synthetic derivative of epothilone B (39) produced by Sorangium cellulosum, was developed by Bristol-Myers Squibb (BMS) as an anticancer drug (administered through injection) that binds directly to (3-tubulin subunits on microtubules, leading to suppression of microtubule dynamics, blocking of cells in the mitotic phase and ultimately leading to... 

Panda D, Rathinasamy K, Santra MK, Wilson L (2005) Kinetic Suppression of Microtubule Dynamic Instability by Griseofiilvin Implications for its Possible Use in the Treatment of Cancer. Proc Natl Acad Sci USA 102 9878... 

Orbit/MAST proteins, also known as CLIP-associated proteins (CLASPs), are involved in the regulation of microtubule dynamics and bind to microtubule plus ends via CLIP115 or CLIP170. Active CLASP suppresses microtubule assembly and axon outgrowth (Lee et al., 2004), whereas activated adenomatous polyposis coli protein (APC see below) promotes microtubule assembly and axon outgrowth. 

Microtubule dynamics alterations also showed impacts on resistance. Goncalves et al. found a 57% increase of microtubule instability in paclitaxel-resistant cell A549-T12 as compared with parental sensitive cell A549, and a 167% overall increase in the more resistant cell A549-T24. ° It is interesting to note that the resistant cells, in the absence of paclitaxel, suffered mitotic block as well, which suggests that both increased or suppressed microtubule dynamics can impair cell function and proliferation. 

When microtubules are depolymerized with nocodazole (Fig. 3c), Mad2 localizes to all kinetochores, which indicates the activation of the checkpoint. If microtubule dynamics are suppressed with taxol while maintaining kinetochore attachments (Fig. 3b), Mad2 localizes to only a few kinetochores... 

Kamath K, Okouneva T, Larson G, Panda D, Wilson L, Jordan MA. 2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules. Mol. Cancer Ther. 2006 5 2225-2233. 

Derry WB, Wilson L, Jordan MA. Substoichiometric binding of paclitaxel suppresses microtubule dynamics. Biochemistry... 

Kamath K, Jordan MA. Suppression of microtubule dynamics by epothilone B is associated with mitotic arrest. Cancer Res. 2003 63 6026-6031. 

The potential of small molecules targeting microtubules as cancer therapeutics was demonstrated by the vinca alkaloids, such as vincristine and vinblastine, which have been used in the clinic for 40 years. At high concentrations (10-100 nM), these compounds depolymerize microtubules, which eliminates the mitotic spindle. At lower concentrations that are used clinically, microtubules remain stable but microtubule dynamics are suppressed. Taxol, which also inhibits microtubule dynamics, is widely used to treat a variety of cancers (reviewed in Ref. [16]. These drugs induce a mitotic arrest, which eventually leads to cell death [17] through mechanisms that are only beginning to be understood [18,19, 20]. 

As a whole, the results presented above indicate that low concentrations of Vinca alkaloids, probably similar to therapeutic concentrations, have an antiproliferative activity that is due to inhibition of mitotic spindle function by changing the dynamics of microtubules rather than by depolymerizing them. A growing body of evidence seems to indicate that, specially in cancer cells, where mitosis regulation is already disrupted, the suppression of microtubule dynamics with mitosis arrest induces a signaling cascade leading to cell death by apoptosis (a type of programmed cell death) [172-174]. 

The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly, rather than microtubule bundling leading to apoptosis, or the blocking of bcl-2 [17]. 

K. Rathinasamy and D. Panda, Suppression of microtubule dynamics by benomyl decreases tension across kinetochore pairs and induces apoptosis in cancer cells, FEBS J., 2006, 273, 4114-4128. 

Smith, J.A., Wilson, L., Azarenko, O., Zhu, X., Lewis, B.M., litdefield, B.A., and Jordan, M.A. (2010) Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry, 49,1331-1337. 

---