Inhibiting cell division

Unregulated cell growth

Cancer, although heterogeneous by its very nature, can be broadly defined as a set of diseases characterised by unregulated cell growth leading to invasion of surrounding tissues and spread (metastasis) to other parts of the body (King et al., 2006). Inhibiting cell division therefore represents a key therapeutic target for cancer.

Characteristics of cancer cells

In their seminal review, Hanahan and Weinberg identified 6 key characteristics of cancer cells, namely: autostimulation; angiogenesis; metastasis; insensitivity to antiproliferative signals; resistance to apoptosis; and limitless replicative potential (Hanahan et al., 2000). This list was recently expanded to include two additional characteristics: reprogramming of energy metabolism and evading immune destruction (Hanahan et al., 2011).

Cell division regulation

Cell division is a tightly-regulated and coordinated process that occurs through the cell cycle. Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases that regulate progression through the cell cycle, and activating mutations of these proteins are implicated in the initiation of tumourigenesis (Collins et al., 2005).

Cell division as a strategy for cancer therapy

The regulation of cell division presents a number of potential therapeutic strategies for cancer treatment. The major mechanism by which conventional chemotherapeutic agents discriminate in favour of targeting tumour cells is by targeting the rapid cell division that is characteristic of most tumour development and progression.

Inhibiting DNA synthesis

Targeting cell division in cancer may involve the inhibition of DNA synthesis (Chabner et al., 1973), induction of DNA damage (Nelson et al., 1994), or the induction of mitotic arrest to induce cell death (Manchado et al., 2012). Inhibition of DNA synthesis One class of chemotherapeutics that specifically targets DNA synthesis is the antimetabolites, which inhibit the incorporation of precursors such as folic acid, and purine and pyrimidine bases into DNA, blocking DNA synthesis.

These drugs are often structural analogues of the precursor in question, which bind to and obscure the catalytic sites of DNA-synthesising enzymes (Rustum et al., 1997; Kaye, 1998). The role of antimetabolites as chemotherapeutics was first put into clinical practice by Farber in 1948, when the folate analogue aminopterin was used to induce remission in leukemia patients (Farber et al., 1948; Kaye, 1998). Purine analogues include fludarabine and cladribine, which have a prominent clinical role in the management of chronic leukemias (Nabhan et al., 2004), and others such as azathioprine which is also used as an immunosuppressant (Sandborn, 1996).

Pyrimidine analogues

Pyrimidine analogues include 5-fluorouracil, which directly inhibits the enzyme thymidylate synthase (Rustum et al., 1997). The most widely-used folic acid antimetabolite is the drug methotrexate, which inhibits dihydrofolate reductase (DHFR), and prevents the biosynthesis of tetrahydrofolate which is necessary for DNA and RNA synthesis (Kremer, 2004), as well as the synthesis of the amino acids serine and methionine.

Topoisomerase inhibition

Indirect and direct DNA damage Another approach for halting the aberrant and rapid cell division of tumours is the inhibition of the topoisomerase DNA repair enzymes. Topoisomerases I and II regulate the topology of coiled DNA by introducing either single-strand or double-strand breaks in the phosphodiester backbone of DNA, respectively (Wang, 1996).

Inhibition of topoisomerases leads to genomic instability and eventual cell cycle arrest and cell death. Common inhibitors include the TopoI-inhibiting campothecin compounds, and the TopoII-inhibiting anthracyclines (such as doxorubicin) and podophyllotoxins (etoposide and its derivatives) (Liu, 1989). Direct DNA-damaging agents act in several ways: by generating free radicals which can induce single- or double-strand breaks in DNA, for example bleomycin and related compounds (Blum et al., 1973; Li et al., 2009); or by catalysing irreversible DNA cross-linking, such as platinum-derived chemotherapeutics including cisplatin (Schaake-Koning et al., 1992).

Mitotic inhibition and arrest

Mitotic arrest Mitotic inhibitors generally act by inhibiting the formation of cellular structures such as the mitotic spindle, which is derived from cytoskeletal components and is essential to the correct distribution of DNA between daughter cells during cytokinesis.

The necessity of functional microtubule assembly for successful cell division presents an attractive therapeutic target for the treatment of tumour growth. Several classes of anti-neoplastic agent have been developed for clinical application which disrupt microtubule dynamics, and are therefore classified as microtubule-targeting agents (MTAs) (Zhou et al., 2005), or microtubule inhibitors (McGrogan et al., 2008).