Linda F. Benedict, Liu, Zhijun, Woltering, Eugene, Hornick, Conrad
Zhijun Liu, Conrad Hornick and Eugene Woltering
Current technologies for the prevention and treatment of cancer are far from being effective at safe, non-toxic doses. Standard chemotherapeutic drugs are all designed to be toxic, harming cancerous and healthy tissues to varying degrees. Targeted therapies such as angiogenic inhibitors directed toward specific receptors or growth-factor pathways offer great hope in managing cancer. Angiogenesis is the process by which new blood vessels grow. All adult angiogenic processes are caused by disease with the exception of a few physiological processes like menses and placental formation. Tumors cannot grow beyond the size of 0.08 inch with-out first inducing new blood vessel formation.
Inhibiting angiogenesis can thus prevent cancer from developing beyond the simple limits of diffusion for oxygen and nutrients.
Scientists at the LSU Health Sciences Center discovered that noni (a tree) fruit juice can inhibit angiogenesis in their human tissue-based Human Placental Vein Angiogenesis Model (HPVAM). Noni juice completely blocked the angiogenic response in this test at 10 percent by volume but was only partially active at a lower concentration. This discovery is certainly exciting since noni fruit is a commonly used dietary item, which minimizes safety concerns.
Noni (Morinda citrifolia) is a Polynesian folk medicine and enjoys a safe and long history of human use. Bark, stem, leaves, roots and fruits have been traditionally used as folk remedies to treat diseases such as hypertension, diabetes and cancer, and are additionally used today for boosting one’s immune system. Noni trees are widely cultivated in many parts of Polynesia and Hawaii.
Noni juice has potential as a perfect cancer preventative for long-term use, despite its unpleasant taste. However, turning this discovery into a practical cancer therapy presents two major obstacles, both typical in the use of botanical extracts for healthcare and therapeutics. First, botanical extracts are either not standardized or standardized without reference to the active ingredients. This has been a key flaw in the quality control of botanical extracts. Manufacturing without knowledge of what is responsible for anti-cancer activities in the noni juice extract risks the loss of the key ingredients in the process and results in inconsistent clinical anti-cancer effects. The commercial availability of multiple brands further complicates things for potential users of this product. To be effective, the active ingredients must be concentrated enough to achieve a therapeutic effect. Extrapolating from current anti-angiogenic studies, if we assume a therapeutic dose of one quart a day, this translates into 180 capsules (500-milligram) a day of freeze-dried, powdered noni juice. A dose of 180 capsules a day is not a practical therapy for cancer.
To overcome these obstacles, a series of experiments was conducted at the LSU AgCenter and the LSU Health Sciences Center. First, we attempted to characterize the active fractions of noni juice. Fractionation of noni juice was performed with column chromatography under the direction of HPVAM tests. Initial fractionation found that one of four fractions (F4) was active. This active fraction was subjected to a second round of fractionation. That subfractionation resulted in the active sub-fraction S100. S100 was subjected to additional fractionation, and two sub-sub-fractions were found to contain active ingredients. Chemical fingerprinting of these fractions gave us a template of key ingredients that must be present in noni products to create an antiangiogenic effect.
Currently, isolation and purification of these active compounds are being performed. The isolated and purified compounds will be structurally described by using nuclear magnetic resonance and mass spectrometry at the LSU Chemistry Department’s facilities in Baton Rouge. Once the active com-pounds are known, they will be used as chemical markers to standardize the extract.
The use of the fractionation processes revealed that 1) noni juice contains more than one active compound responsible for the observed antiangiogenic activity and 2) the active ingredients are in very low concentrations. Clearly, we need to develop a commercially viable processing method that can retain and raise all the active ingredients to therapeutic concentrations.
As the first step in this process, we developed a simple, single-step method to derive a highly concentrated noni extract called Super Noni. Super Noni represents 3 percent by weight of native, freeze-dried noni juice. At a 0.1 percent solution, the Super Noni extract completely inhibited human angiogenesis (Figure 1), whereas 10 percent by volume of native, freeze-dried and reconstituted noni juice was required to produce the same antiangiogenic effect. This increased potency of 100-fold is due to the removal of 97 percent of the inactive ingredients in the noni juice, yielding a net 33-fold increase in the concentration of active ingredients. This disproportionate increase in potency may have occurred because some substances that nullify the effects of angiogenesis may have been removed during processing or possibly as a result of a synergistic effect among the active ingredients in the Super Noni extract.
Assuming a therapeutic dose of one quart a day (equivalent to 3.17 ounces of freeze-dried noni juice powder), one would require 180 capsules (500 milligrams) a day of the noni juice but only six capsules (about 0.2 ounces) of Super Noni extract a day. Thus, the Super Noni product is extremely practical for clinical use. An antiangiogenic extract may not be therapeutically effective if underdosed, and this under-dosing is most likely to be caused by low levels of the active ingredients in the extract. Yet large doses (for example, 180 capsules a day) are not feasible. The exact therapeutic dosing regimen will have to be determined in human clinical Phase I trials, but it is obvious that this refined noni extract offers a great advantage in designing clinically effective yet practical dosing regimens for cancer therapy and prevention trials.
The Super Noni concept makes commercial sense and presents a viable commercial opportunity for product development in the area of medical foods and nutraceuticals.
The collaborative work of these researchers presents convincing scientific evidence and a botanical prototype product for treatment and prevention of re-occurrence of tumors, malignant or benign, that rely on angiogenesis to grow and spread. A method is being developed in tissue culture settings to propagate noni plants. Since noni is a tropical plant, cultivation of this plant will have to be limited to greenhouses in Louisiana.
Zhijun Liu, Associate Professor, School of Renewable Natural Resources, LSU AgCenter, Baton Rouge, La.; Conrad Hornick, Professor, Department of Physiology, LSU Health Sciences Center, New Orleans, La.; Eugene Woltering, James D. Rives Professor, Department of Surgery, the Stanley S. Scott Cancer Center, the Neurosciences Center of Excellence, and the Veterans Administration Medical Center, LSU Health Sciences Center, New Orleans, La.
(This article was published in the winter 2005 issue of Louisiana Agriculture.)