Mechanism of action of ixabepilone and its interactions with the βIII-tubulin isotype

  title={Mechanism of action of ixabepilone and its interactions with the $\beta$III-tubulin isotype},
  author={Manu Lopus and Gregoriy Smiyun and Herbert P. Miller and Emin Oroudjev and Leslie Wilson and Mary Ann Jordan},
  journal={Cancer Chemotherapy and Pharmacology},
Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. [] Key Result The βIII isotype of tubulin is associated with drug resistance and tumor aggressivity. We found that removal (in vitro) and knockdown (in cells) of βIII-tubulin led to increased inhibition of microtubule dynamic instability by ixabepilone.

Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype.

aberibulin suppressed the dynamic instability behavior of βIII-depleted microtubules more strongly than and in a manner different from that of micro Tubules containing βIII tubulin.

Elucidation of the anticancer potential and tubulin isotype-specific interactions of β-sitosterol

The data show the tubulin-targeted anticancer potential of β-SITO, and its potential clinical utility against βII and βIII isotype-overexpressing neoplasms.

βIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel

Cabazitaxel may be unusual among microtubule-targeted drugs in its superior anti-tumor efficacy in tumors overexpressing βIII-tubulin.

2-(m-Azidobenzoyl)taxol binds differentially to distinct β-tubulin isotypes

Analysis of the sequences of β-tubulin near the Taxol binding site indicated that, in addition to the M-loop that is known to be involved in drug binding, the leucine cluster region of βIII- Tubulin contains a unique residue, alanine, at 218, compared with other isotypes that contain threonine.

Astragalus membranaceus–Derived Anti-Programmed Death-1 Monoclonal Antibodies with Immunomodulatory Therapeutic Effects against Tumors

Experimental results indirectly indicate the ability of APS to induce specific antibodies associated with the immune checkpoint system and the potential benefits for improving immunity in humans.

Safranal Inhibits HeLa Cell Viability by Perturbing the Reassembly Potential of Microtubules

As the acetylation pattern of the safranal‐treated microtubules revealed, unlike many tubulin‐targeted agents, the compound did not appear to induce persistent stabilization of micro Tubulin, indicating its ability to interfere with the nucleation potential of tubulin.

Chemotherapy reaction induced by ixabepilone, a microtubule stabilizing agent, mimicking extramammary Paget's disease in a patient with breast carcinoma

A case of a 67‐year‐old female with locally advanced metastatic breast cancer, who initially presented with an extensive reticulated erythematous patch on the trunk caused by intravascular metastases confirmed by a skin biopsy, and the demonstration of epidermal mitotic arrest caused by ixabepilone is without precedent.



Ixabepilone: targeting βIII-tubulin expression in taxane-resistant malignancies

The significant antitumor activity of ixabepilone in taxane-resistant tumors may be related to its preferential suppression of the dynamic instability of α/βIII-microtubules in cells expressing high levels of βIII-tubulin.

Altered TUBB3 expression contributes to the epothilone response of mitotic cells

The results show that the expression of TUBB3 contributes to the cellular response to epothilones, putatively by having an impact on the mt dynamics.

Development of other microtubule-stabilizer families: the epothilones and their derivatives

The preclinical and clinical development of epothilones and their derivatives across a variety of cancer types are discussed, which have properties favoring their development as anticancer agents.

Interaction of estramustine with tubulin isotypes.

In both bovine brain microtubules and cytoskeletal proteins from human prostatic carcinoma cells, the incorporation of [14C]estramustine into the beta III isotype of tubulin was found to occur with a reduced efficiency compared to that of the other beta- Tubulin isotypes and alpha-tubulin.

Suppression of microtubule dynamics by epothilone B is associated with mitotic arrest.

The effects of epothilone B on microtubule dynamics are remarkably similar to those of paclitaxel, suggesting that both drugs induce mitotic block by a similar mechanism.

βII-Tubulin and βIII-Tubulin Mediate Sensitivity to Peloruside A and Laulimalide, but not Paclitaxel or Vinblastine, in Human Ovarian Carcinoma Cells

It was concluded that the increased βII- and βIII-tubulin contributed significantly to the resistance phenotype, along with the tubulin structural mutation, and that the altered isotype effect was binding site specific.

βIII-Tubulin Induces Paclitaxel Resistance in Association with Reduced Effects on Microtubule Dynamic Instability*

The results suggest that overexpression of βIII-tubulin induces pac litaxel resistance by reducing the ability of paclitaxel to suppress microtubule dynamics, and suggest that endogenous regulators of microtubules dynamics may differentially interact with individual tubulin isotypes, supporting the idea that differential expression of tubulin wasotypes has functional consequences in cells.

Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

Data indicate that the effect of class III β-tubulin overexpression may depend on where the drug’s binding site is located on the tubulin, which highlights for the first time the potential key role of targeting the colchicine-binding site, to develop new treatment modalities for taxane-refractory breast cancer.

Maytansinoid-Antibody Conjugates Induce Mitotic Arrest by Suppressing Microtubule Dynamic Instability

The results indicate that free maytansinoids, antibody-maytans inoid conjugates, and their metabolites exert their potent antimitotic effects through a common mechanism involving suppression of microtubule dynamic instability.