Current Cancer Drug Targets - Volume 2, Issue 4, 2002

The influence of natural products upon drug discovery in general has been quite impressive, one only has to look at the number of clinically active drugs that are in use in cancer therapy to see how many either are natural products or have a natural product pharmacophore. What is now becoming quite apparent is that materials from natural sources are excellent probes (indicators) for cellular targets that when modulated, may well have a deleterious effect upon the cycling of a tumor cell through the conventional cell cycle. If the particular target is not expressed in normal cell cycling, then a directed “perturbation” of the tumor cell's cycle may well lead to a novel method of treatment for specific tumor types. In this review we have not attempted to be exhaustive but have given a current overview of how natural products from marine, microbial and plant sources have permitted in-depth analyses of various parts of the cell cycle under varying conditions with the ultimate aims of attempting to “control or perturb” the cycling of tumor cells in a fashion that permits their ultimate removal via cellular death, with a minimum of trauma to the host.

The cell cycle is a highly conserved and ordered set of events, culminating in cell growth and division. It is tightly controlled by many regulatory mechanisms that either permit or restrain its progression. The main families of regulatory proteins that play key roles in controlling cell cycle progression are the cyclins, the cyclin dependent kinases (Cdks), their substrate proteins, the Cdk inhibitors (CKI) and the tumor suppressor gene products, p53 and pRb. Many cell cycle control genes, when deregulated, can cause cells that are not dividing to enter the cell cycle and begin to proliferate leading to cancer development. They do so by interfacing with the basic cell cycle-regulatory machinery to activate cell cycle entry. There is at present much optimism about the possibility of finding anticancer drug treatment strategies that modulate cell cycle regulatory molecules. Candidate targets for such strategies include crucial cell cycle molecules involved in G1 to S phase or G2 to M phase transition. This review will outline the basic regulatory machinery responsible for catalyzing cell cycle entry and describe the latest advances made in the field of cell cycle regulation. The basis of targeting the cell cycle particularly the Cdks as an approach to developing novel, specific and perhaps more effective anticancer treatments will be discussed. Examples of novel cell cycle-targeting agents that are in, or are close to being in clinical trials will be provided.

The anticancer properties of histone deacetylase inhibitors have been known for some time. However, it is only recently that the functional identities of the intracellular targets mediating the anticancer properties have started to be revealed. These targets appear to play significant roles in cell cycle control, apoptosis and differentiation. Importantly, the modulation of these activities is likely to be mediated by alterations in the acetylation status of both histone and non-histone targets. Identification of these targets, and the specific histone deacetylase enzymes that modulate them, is an important step in designing rationalbased therapies for the treatment of cancer. In this review we discuss the state of progress in identifying the molecular pathways / events mediating the anticancer activity of histone deacetylase inhibitors.

The function of gene products can be altered at many levels, including the mutation of gene sequence and the change in steady state levels of mRNA and / or protein by various mechanisms. The cumulative malfunction of specific gene products underlies many pathological conditions such as the multi-step and multi-cause acquisition of cancer. Here we discuss two oligonucleotide-based strategies in which these compounds target defective gene products acting either as antiprotein or anticode agents. The SELEX technique (systematic evolution of ligands by exponential enrichment) is an antiprotein approach in which nuclease-resistant DNA or RNA aptamers are selected by their ability to bind their protein targets with high affinity and specificity of the same range as antibodies. Such inhibitors were previously evolved against a great variety of targets, including receptors, growth factors and adhesion molecules implicated in the genesis of some kinds of cancer. Moreover, some results have already been obtained in animal models. The antigene technology interferes with earlier steps in the information flow leading from gene to protein. In this approach selective gene silencing is provided by the formation of stable and specific complexes between triplex forming molecules and their DNA targets. The feasibility of this strategy as well as a molecular mechanism for the action of antigene oligonucleotides has been demonstrated in cellular systems and in vivo. The use of oligonucleotide drugs (of either the antiprotein or the anticode type) as a viable approach to cancer therapy is limited by some common problems that will be discussed.