Natural Product Mixture Screening Project
Summary
New Earth BioMed is initiating a large screening program in which thousands of natural product mixtures will be tested in complex cell cultures in order to identify those that could be useful in cancer therapy. A key technology used in testing will be a new laser-based system that allows fast measurement of drug-induced changes in three-dimensional cultures without disturbing them in any way. For more information about the laser system, see the
laser bioassay description.
Background
Roughly 77 percent of FDA-approved cancer drugs derive either directly or indirectly from plant compounds [
4]. Although thousands of natural compounds inhibit cancer cells in-vitro, exceedingly few exhibit the degree of potency and type of pharmacologic profile that result in successful single-agent anticancer drugs.
For example, the large cytotoxicity screening program administered by the Developmental Therapeutics Program at National Cancer Institute (NCI) has tested more than 500,000 compounds against cancer [
1], and from this only a handful have been successfully developed as single-agent drugs. Many of the tested agents were natural products. It is our belief that the success rate of a screening program could be markedly increased by focusing the testing procedure on mixtures of compounds, rather than single agents.
Most safe natural products (such as those found in foods, spices, and medicinal herbs) that inhibit cancer do so at moderate potency—too low of potency to be of interest in traditional drug discovery programs. However, when used in mixtures, these compounds can exhibit additive and synergistic effects, rendering them more attractive as therapeutic agents. In some cases, they can also act synergistically with approved chemotherapy drugs. The use of multiple constituents can lead to greater control over efficacy and safety [
2,
3].
Targeting the Protein Network
Recent developments in biology, bioinformatics, and related fields have demonstrated that the behavior of cancer cells, as well as normal cells, is governed by a complex and dynamic internal network of interacting proteins. In the emerging systems biology view, the logical target for cancer therapy is the network itself. This is in contrast to typical drug discovery programs that are focused on identifying a single protein as the target for therapeutic intervention.
Adopting the network-as-target approach, allows for greater flexibility in drug design than is possible for single-target approaches. For example, mixtures can be used to affect many processes via multiple proteins. Some mixture constituents could be chosen to inhibit cancer cell proliferation, while others could be chosen to inhibit invasion, or inhibit the ability of cancer cells to pump drugs out of the cell.
Cancer cells are intimately connected to and communicate with their immediate surroundings. Indeed, the clinical progression of cancer sometimes depends on the actions of neighboring cells. An example is the growth of new blood vessels towards a tumor in a process called angiogenesis. Tumors require development of a blood supply if they are to grow beyond a small size. Thus cancer cells are not the only cell type that could be targeted during therapy. To allow for targeting diverse proteins and cells, mixtures are nearly indispensable.
NEBM is exploring an extreme version of mixtures, which we term distributed polypharmacology (DPP). Polypharmacoloy implies that multiple active compounds are employed, and distributed implies that the total effect results from small influences of a large number of agents. Mixtures in DPP could contain dozens of active compounds, each at low concentrations. In contrast, typical drug mixtures, such as used in combination chemotherapy, contain only two or a few components and each is used at the highest possible dose.
With rapid improvements in all areas of bioscience and analytical technology, our ability to rigorously demonstrate the effects of a compound within a mixture is steadily increasing. The laser bioassay system that NEBM is developing is one step towards that goal. For more information on the mixture screening program, as well as the laser bioassay system, please see our
Roadmap.
Bibliography
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[3] Lehar, J., Krueger, A. S., Zimmermann, G. R., Borisy, A. A. Therapeutic selectivity and the multi-node drug target. Discov Med, 2009;8(43):185-90. URL: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?cmd=prlinks&dbfrom=pubmed&retmode=ref&id=20040268.
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