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Cancerous tumor cells are characterized by their rapid rate of cell division, which is no longer controlled as in normal tissues. Somatic cells of the body normally undergo a resting period during the G0 phase of the mitosis, and differentiate into functional cells no longer capable to divide.
In case of active tumors, the cells are activated by specific kinases (enzymes that add phosphate groups to other molecules) and enter a phase of relentless proliferation. Such cells typically display abnormalities in the mechanisms that regulate normal cell division, differentiation and survival.
In order to accommodate these changes, malignant cells show signs of morphological and cytoskeletal alterations. Prevention of such restructuring and subsequent cell division is a key mechanism of the drug paclitaxel, which makes it an effective treatment for aggressive cancers.
In general, structural proteins do not represent important drug targets. One of the exceptions is a protein named tubulin, a heterodimer formed by an alpha and beta-subunit with 40% sequence identity and virtually identical three-dimensional structures.
Tubulin polymerizes into small tubes called microtubules, which are responsible for mitosis, cell movements, preservation of cell shape, signal transmission, as well as the intracellular trafficking of organelles and macromolecules. Microtubules arise from the specific longitudinal self-assembly of tubulin dimers to form protofilaments, which interact to constitute the wall of these structures.
Paclitaxel stabilizes microtubules and reduces their dynamicity, promoting mitotic halt and cell death. Unlike other drugs that act on microtubules and induce the disassembly of microtubules (for example vinca alkaloids), paclitaxel boosts the polymerization of tubulin and overproduction of microtubules. The drug binds to the N-terminal 31 amino acids of the beta-tubulin subunit in the microtubule.
Hence microtubules that are formed under the influence of paclitaxel are exceptionally stable and dysfunctional, causing the death of the cell via disruption of the normal microtubule dynamics and vital interphase processes. Simply put, an affected cell can no longer use its own cytoskeleton in a flexible manner.
Further research has shown that paclitaxel drug plays a vital role by binding to a anti-apoptic agent that prevents cell death, Bcl-2 (B-cell Lymphoma 2), and stopping its function. The drug attacks the serine residues at site 70 and 87 while they act on microtubules; therefore being a tubule poison, this drug can also kill cancer cells that express Bcl-2.
Paclitaxel induces the expression of the genes for the tumor necrosis factor alpha (TNF-α) and interleukin 1, as well as several other inducible genes in macrophages. It causes a reduction in the surface expression of TNF-α receptors as well. Such properties add significantly to its antitumor efficacy.
In addition to his main mode of action as a microtubule stabilizator, paclitaxel may also act as a molecular mop by sequestering free tubulin, thus effectively depleting the cell’s supply of tubulin monomers and dimers. This activity can also trigger apoptosis (the process of programmed cell death).
The efficacy of paclitaxel is significantly limited by the development of acquired resistance. Two principal mechanisms of resistance have been described for this drug. Some tumors are known to contain tubulin subunits with a reduced ability to polymerize into microtubules and inherently slow rate of microtubule assemblage, which can be normalized by paclitaxel and other taxanes.
In the second mechanism, membrane phosphoglycoproteins that function as drug-efflux pumps are amplified. The multidrug-resistant phenotype of tumor cells can result in varying degrees of cross-resistance to natural products with bulky structures, i.e. a group of drugs where paclitaxel can be found as well.
Recent research has shown that an increased expression of TNFAIP1 (tumor necrosis factor alpha-induced protein 1) results in acquired resistance to paclitaxel. TNFAIP1 competes with paclitaxel for binding to beta-tubulin, preventing in turn tubulin polymerization, cell cycle arrest and ultimate cell death.