Plant-Based Anticancer Drug Development: Advancements and Hurdles

In addition to the practices of the Chinese, Greeks and Romans, one of the oldest and best-known records of civilized medicine was described in the Egyptian ‘Ebers Papyrus’ (circa 1500 BCE), which documented over 700 drugs, mostly of plant origin [1]. Throughout different civilizations humans have relied on nature to accommodate their basic needs, not the least of which are medicines for the treatment of a wide spectrum of diseases from coughs and colds to parasitic infections and inflammation.


tics; Phytochemicals; Chemopreventive agents
In addition to the practices of the Chinese, Greeks and Romans, one of the oldest and best-known records of civilized medicine was described in the Egyptian 'Ebers Papyrus' (circa 1500 BCE), which documented over 700 drugs, mostly of plant origin [1]. Throughout different civilizations humans have relied on nature to accommodate their basic needs, not the least of which are medicines for the treatment of a wide spectrum of diseases from coughs and colds to parasitic infections and inflammation.
A sobering statistic has recently shown that a person born in the United States today has a 41% lifetime risk of being diagnosed with cancer. This alarming fact has urged the health care community to identify effective methods of cancer prevention [2]. Cancer cells exhibit deregulation in multiple cellular signaling pathways, yet all cancers share a number of common hallmark capabilities, such as genetic instability, self-sufficiency in growth signals, insensitivity to anti-growth signals, avoidance of apoptosis, unlimited replication, sustained angiogenesis, and tissue invasion and metastasis [3]. Therefore, utilizing specific agents to target single pathways is a tactic that frequently fails in cancer therapy. Genetic instability produces intra-tumoral heterogeneity that enables adaptive resistance. Combination chemotherapy that targets a number of distinct molecular mechanisms is therefore preferable and considered more promising, but the use of multiple agents is often constrained due to corresponding increases in toxicity [4].
Accumulating evidence has shown that some natural products such as saffron [5,6] and curcumin [4] and many others have growth inhibitory and apoptosis inducing effects both in vivo and in vitro. Frequently this sort of action is made possible by site-specific action on multiple cellular signaling pathways without causing undesired toxicity in normal cells. Therefore, these non-toxic natural agents could be useful in combination with conventional chemotherapeutic agents for the treatment of human malignancies with lower toxicity and higher effectiveness.
The use of natural products has increased in the United States with approximately 18% of American adults in 2007 reported using natural products beyond a basic multivitamin. Individuals use natural products for a variety of health reasons, including treating and preventing disease, maintaining health, and promoting wellness [2]. So the potential of natural products is increasingly being recognized. At the same time, natural products remain one of the most important sources of new drug leads with more than half of all new chemical entities launched in the market are natural products or their derivatives or mimetics. In fact the borderline between food and medicine is as fuzzy as it is ever been [7].
The efficacy of natural products as chemopreventive agents for primary and tertiary cancer prevention has not yet been established. Observational studies have suggested that various vitamins, minerals, and dietary components reduce the risk of developing specific cancers. However, clinical trials have not always supported these observations and/or the trials have not been conducted to test the efficacy of the natural products as chemopreventive agents. And although there is also a common perception that natural products are safe because they are "natural", a natural product is not necessarily a safe product. So, current guidelines from the American Institute of Cancer Research, the American Cancer Society, and the Society for Integrative Oncology recommend against the use of dietary supplements for cancer prevention based on the current evidence [2].
Unfortunately, how well these compounds might work in the inhibition of cancer has yet to be rigorously tested in Phase IV tests. There is also little known about the interactions of naturally occurring chemical (phytochemical) with other drugs prescribed by physicians and used by patients for the treatment of cancer or other diseases. Thus our current knowledge has many gaps that will need to be resolved before such compounds can receive approval by regulatory agencies, broad acceptance by the medical community and join other pharmaceuticals on drugstore shelves [8].
Nonetheless, our ability to address these knowledge gaps is rapidly improving. A large number of robust and specific biochemical-and genetics-based screens using transformed cells, a key regulatory intermediate in a biochemical or genetic pathway, or a receptor-ligand interaction (often derived from the explosion in genomic information since the middle 1990s) are now in routine use. These screens are enabling precise detection of the actions of bioactive components of natural product extracts [1]. And since many phytochemicals have characteristics that will allow them to be combined with far less danger of toxicity and a much lower risk of invoking multiple drug resistance, it makes the idea of targeting a broad-spectrum of mechanisms in cancer cells (using complex combinations of chemicals) a very real possibility.
Historically, the complexity of cancer necessitated an incredible amount of specialization that has led to very narrowly scoped research. In the past two decades this approach has resulted in significant advances in our understanding of the disease, but unfortunately this trend towards specialization has meant that very few researchers ever have the freedom or the opportunity to undertake projects that are broad in scope. For similar reasons, many conventional research funding agencies and journals have not been all that supportive of anticancer research involving too many biologically active ingredients due to concerns over the number of variables that can be controlled in any given experiment. But we need to overcome these systemic barriers if we are going to match the complexity of the disease with an approach to prevention and therapy that is equally complex (i.e., capable of shutting down a wide range of immortalized cells by acting on many different mechanisms and pathways).