From "tajy" tea to beta-lapachone

AN INDIAN TRADITION THAT INSPIRES NEW CANCER DRUGS: FROM "TAJY" TEA TO BETA-LAPACHONE

The Southamerican Guarani natives have used Pau d'arco, or Lapacho ("tajy" in the vernacular), tea for the treatment of wounds, inflammation and even cancer. The scientific community has taken note of this custom: there have been numerous experiments to discover specifically which among all of its chemicals are benign, in order to extract, concentrate and purify them.

AGAINST INFECTIONS

In a study released in 1993, Claudia Anesini and Cristina Pérez examined 132 folk medicinal plant extracts of Argentina looking for activity against microbes. Lapacho bark produced some of the most active extracts. Klaus Müller, Andreas Sellmer and Wolfgang Wiegrebe discovered in 1999 that by its potent activity against the growth of some human skin cells called keratinocytes, some components derived from lapacho show promise as effective agents against psoriasis, a disease that affects the skin and joints. One of the substances present in lapacho, lapachone, showed activity comparable to the antipsoriatic drug "Anthralin". However, as observed with "Anthralin", the treatment of certain cells with this potent lapacho compound also caused a remarkable membrane damage.

In 2000 it was discovered that certain compounds show anti-inflammatory properties. Results of other experiments reported in that year confirm a trend of killing the parasite "Trypanosoma sp." by these compounds, an indicative that they can be used as a guide to the discovery of molecules with potential against Chagas disease. Another group of researchers found similar properties by certain synthetic derivatives of Lapacho. These derivatives are potential candidates for further experimental tests.

In 2001 Aida Portillo and colleagues tested 14 Paraguayan plants used in traditional Medicine to treat skin diseases. Against 11 different types of fungi, the one which showed the highest activity was lapacho. In another study an aqueous extract of the inner bark was prepared and was administered orally to mice. Edema was inhibited by about 13%. Acute toxicity was low in mice.

Another group of researchers tested the activity of potassium salt from the lapachol compound, also present in Lapacho, against certain species of snails and their eggs. They found a strong combative effect. They also tested lapachol derivatives against certain forms of "Trypanosoma cruzi", the origin of Chagas disease, and they saw relevant properties, killing up to 95,7% of the parasites.

In 2003 Thelma Machado and colleagues used extracts from 14 plants of the Brazilian traditional Medicine, including lapacho, used to treat infectious diseases. These scientits sought potential properties against certain bacteria important from the medical point of view because they are resistent to antibiotics. The results indicate that this natural product can be an effective potential candidate for developing new strategies for treatment of infections unresponsive to the antibiotics used so far.

AGAINST CANCER

In 1975 Maria da Consolação Linardi and colleagues discovered a compound which extends lapachol activity, making it effective against leukemia in mice. After a 9-day treatment, life expectancy increased by 80%. In 1997 it was discovered that it significantly attacks certain types of lung cancer and colon cancer.

Through "in vitro" studies (that is, in an artificial environment) it was discovered in 1997 that lapachol does have anticancer effects, but this activity was inhibited by vitamin K. Results from 2001 suggest that lapachone can damage the DNA of cancer cells.

In 2002, Jiang Zhiwei and Jane Hodgeland patented a novel process to synthesize the related substance beta-lapachone. The process comprises the conversion of the industrial raw material into lapachol. Then, lapachol is converted to beta-lapachone by a treatment with sulfuric acid and purified by recrystallization from ethanol. This new process is extremely simple and produces beta-lapachone of excellent quality and in large quantities. That year a synthesis and preliminary pharmacological evaluation of new substances structurally related to lapachol were also completed. The pharmacological tests provided evidence of significant biological activities, including effects against proliferation of a type of breast cancer cells, against infection by herpes simplex type-2 virus, and even against some effects of snake venom.

A derivative showed activity similar to those of benzodiazepine drugs, suggesting a novel structure with effects on neurons.

In a study published in 2003 some extracts exhibited strong antioxidant effects.

Other findings, by Dai-Yean Choi and colleagues, suggest that the inhibition of cell proliferation of human liver cancer and bladder carcinoma induced by beta-lapachone is associated with the induction of a certain type of cell death. That year the structures of some compounds from lapacho were discovered by high-field, nuclear magnetic-resonance spectroscopy, and it was found that the biological activity of the lead compound, lapachol, and a related compound, alpha-lapachol, and other substances may explain, at least in part, the effects attributed to the crude drug in Paraguayan folk Medicine.

Results of other published studies demonstrated some compounded mechanisms used by beta-lapachone to act selectively and would explain some of its anticancer effects. Minoru Suzuki and colleagues discovered in 2006 that, in radiotherapy, radiation firstly leaves the cells sensitive to beta-lapachone by altering the regulation of a certain substance, and secondly beta-lapachone leaves cells sensitive to radiation by inhibiting repair of radiation damage. The combination of beta-lapachone with radiotherapy is a potentially promising modality for treating cancer in humans.

Finally, in June 2007 Erik Bey and colleagues discovered the mechanism of action of beta-lapachone and devised a way to use it in an individualized therapy.

"TAJY" TEA IS NOT THE SAME THING AS BETA-LAPACHONE

Robert Morrison et al. studied in 1970 the toxic effects of orally-administered lapachol in rodents, dogs and monkeys. Deaths occurred in monkeys, and other signs in dogs and monkeys, including moderate to severe anemia and diseases with frightening names such as reticulocytosis, normoblastosis, bilirubinuria, and proteinuria. Additionally, effects with non-encouraging names such as transient thrombocytosis, leukocytosis and some "high activity of alkaline phosphatase serosa", whatever it be, ocurred, besides other effects.

In 1974 Jerome Block and others performed clinical studies in 19 patients with advanced nonleukemic tumors, and in 2 patients with a recurrent, chronic type of leukemia. All patients had previously received a variety of therapies, which failed. This time they were given lapachol. A patient with advanced breast cancer, in metastases, had an improvement in a hip injury, but no change in numerous other bony lesions. All other patients either remained clinically unchanged in their conditions or their disease advanced. They also reported that the toxicity observed in patients participating in clinical trials included nausea and vomiting and other effects at very high doses. The trials had to be suspended, because of an undesirable anticoagulant effect of the substance and because in order to obtain some beneficial effect, doses way too high were required, with consequent nausea and vomiting.

In 1989 a similarity of its anticoagulant properties to the properties of two substances called sulfaquinoxaline and warfarin were found. These results provide guidance on how they work.

In February 1985 pau d'arco, or lapacho, was banned by the Federal Health Protection Branch of Canada until their distributors prove it is safe and effective, adding that the federal Food and Drug Act does not allow lapacho to be advertised or sold as a treatment, prevention or cure for certain diseases, including cancer. An analysis of the bark of three lapacho species showed in 1988 that, unlike what happens in its timber, it does not contain lapachol nor the substance dehydro-alpha-lapachone as its main constituents. Depending on the species, these compounds were either present in very small amounts or entirely absent. Instead, three lapachol derivatives were detected; their physiological properties appear to be very similar to those of lapachol.

In 1998 an analysis of 12 lapacho products available in Canada revealed that only one contained lapachol. In 1988 it was discovered that, although it has been considered a potential agent against malaria, lapachol exhibits very low activity.

The results of the experiments of Martha Guerra and others in 1999 showed that pregnant rats are not affected by lapachol but their embryos are, with fetal mortality of 100%. Data from experiments in 2001, 2002 and 2006 confirmed the strong abortifacient effect of lapachol in rats.

In the journal "CA: A Cancer Journal for Clinicians", September-October 1993, nutritional therapies as methods for cancer administration are questioned. It reports that although dietary measures can be useful in preventing certain cancers, there is no scientific evidence of any nutritional regimen that is appropriate as the main treatment for cancer. It cites the pau d'arco or lapacho tea treatment, along with vitamin C treatments, a so-called Gerson diet, Hoxsey herbal therapy, macrobiotic diet, Manner metabolic therapy and Kelley metabolic therapy. Some of these treatments involve a diet that is nutritionally inadequate. Others involve potentially toxic doses of vitamins or other substances. Some are very expensive. All carry the risk that patients abandon other treatments that are effective. Therefore, the American Cancer Society recommends that "nutritional cancer cures" be avoided.

Aldo Loup.

Originally published in ABC Color, on 23 September 2007. Photo: "Tabebuia impetiginosa", or Pink Lapacho, at the waterfront of Corrientes, Argentina, in 2006. Credit: Copyright © 2006 Carla Antonini (original license, of the photo only, obtained at: http://creativecommons.org/licenses/by-sa/2.5/ar/deed.en), via Wikimedia Commons.