Microtubule stabilisation

Cell cycle breakdown leads to uncontrolled proliferation of cells

In human cells, cell replication is a complex process controlled by a large number of genes. These genes can be divided into three categories: genes that promote cell proliferation, genes that suppress it and genes that signal when damaged cells should undergo apoptosis. The accumulation of mutations in these genes, by the action of genetic or environmental factors, can cause the cell to transform to a cancer cell, a state in which it will no longer respond to many of the signals that control cellular growth and death.

This leads to an uncontrolled proliferation of cells within tissues that eventually leads to the formation of a tumour. Based on their ability or lack thereof to spread to other tissues, tumours can be classified as malignant and benign. Malignant tumours, unlike benign ones, have lost their dependence on their originating tissue, and can thus spread to their organs and become life threatening.

Historically, a great number of the medications used to treat cancer have been cytotoxic compounds, which tend to preferentially target populations of cells in active replication, such as those found in tumours. Although the recent ongoing elucidation of the pathways relevant to each type of cancer has permitted the development of more selective drugs, cytotoxic agents remain in the forefront of cancer treatment. Very important amongst these are drugs that act through microtubule stabilisation.

The biological significance of microtubules

Microtubules are a part of the cytoskeleton, the molecular apparatus that holds the cell together. They are polymers formed by the repetition of a dimer consisting of two globular proteins, called α- and β-tubulin; these dimers can associate to form protofilaments, which can then further associate to form a microtubule. Apart from functioning as mechanical support for the cell, they are involved in a number of other processes, such as intracellular transport and cell division.

In mitosis, the main type of cell division operative in adult somatic cells, a cell which has duplicated its chromosomes is divided into two identical daughter cells. Microtubules hold a fundamental role in this process, as they constitute part of the mitotic spindle, a structure which segregates the divided chromosomes between the two daughter cells. The lengthening and shortening of microtubules through polymerization and depolymerization of the αβ-tubulin heterodimers is essential to this process. Various proteins in the cell promote microtubule assembly and stabilisation, while others favour depolymerization. The precise interplay between these two kinds of factors is crucial to successful cell replication. Therefore, by altering microtubule polymerization, the function of the mitotic spindle is also affected and, consequently, chromosome segregation is disturbed, inhibiting cell division.

Targeting microtubules with natural products

There are several natural products which interact with microtubules. Some destabilise microtubules (colchicine, halichondrins, combretastatines and the Vinca alkaloids are examples) while others such as taxol, discodermolide, sarcodictyins, laulimalide are microtubule-stabilising agents. Some of these (taxol, vinca alkaloids) are marketed drugs.

Despite the usefulness of natural products in cancer treatment, they exhibit non-ideal pharmacokinetic profiles, while their complexity hinders large-scale production. This along with the emergence of drug resistance proves the necessity of detailed structure-activity relationship studies that will allow the design of improved anti-cancer drugs. OxIOSCR aims to address this by providing methodology that will allow easy access to analogues of a number of natural products that display antiproliferative activity.