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Human Beta III Tubulin: The Mystery and the Critical Revision
Abstract
Microtubules are the highly dynamic cell structure component composed of alpha-beta Tubulin dimers, involved in diversified cellular function like motility, cell shape, intracellular trafficking and most importantly, cell division. Tubulin or Microtubule Associated Proteins (MAPs) mutations lead to defective cytoskeletal architectures inducing diseases. This Tubulin-microtubule system is a well established cancer drug target. Anti-Microtubule drugs can be classified into two groups namely microtubule-stabilizing and microtubule-destabilizing agents. The stabilizing one binds to the tubulin polymer stabilizing the microtubules and the latter binds to the tubulin dimers and keeps the microtubules at depolymerized state. Alteration of Tubulin-microtubule equilibrium disrupts the mitotic spindle during mitosis creating halt in the cell cycle leading to cancer cell death. Established microtubule inhibitors unfortunately have severe drawbacks like neurological and bone marrow toxicity and drug-resistance emergence in tumor cells. Several natural and synthetic microtubule-targeting agents showed great antitumor activity and increased potency in killing cancer cells. Ombrabulin, Cryptophycins, Soblidotin, Epothilones, Discodermolide, D-24851 and Combretastatins are some of the compounds used in clinical trials. Some of them exhibit good anticancer activity (anti-angiogenic or anti-vascular) and others showed the potential to overcome multidrug resistance, supporting their possible development in cancer chemotherapy. A novel series of paclitaxel derivatives generation have been designed and synthesized having differential affinity depending on the β-tubulin isotype. Strong Tubulin Beta III-(TUBB3) expression was most frequently found in various brain tumors, lung cancer, renal cell carcinoma, malignant melanoma, and pancreatic adenocarcinoma etc. On one hand, Class III β-tubulin is recognized as a prognostic biomarker in oncology and on the other hand it is an indicator of resistance to taxanes. As it is overexpressed in most aggressive and resistant tumors, the design of a βIII-tubulin targeted compounds is expected to enhance the anticancer activity having reduced toxicities.
Keywords
References
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