By David N. Leff

Australians call them ¿wattles.¿

They are the Acacias ¿ small trees that blanket their subcontinent, particularly its dry, desert regions. For that matter, acacia plants ¿ of which there are some 800 species ¿ occur over much of the world. One African variety gives the world gum arabic ¿ the sticky substance that exudes from their stems to make the familiar goo of adhesives, pharmaceuticals, inks and whatever.

Now an Australian species, Acacia victoriae, seems about to endow humanity with an anticancer compound, called avicin. ¿The taxonomic name of this small tree, A. victoriae,¿ observed cancer researcher Jordan Gutterman at the University of Texas M.D. Anderson Cancer Center in Houston, ¿has nothing to do with the Australian state of Victoria. Rather, it was discovered near the Victoria River in the state of Queensland.¿

Gutterman is senior author of two consecutive papers in today¿s Proceedings of the National Academy of Sciences (PNAS), dated Sept. 25, 2001. The first bears the title: ¿Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), suppress H-ras mutations and aneuploidy in a murine skin carcinogenesis model.¿

The follow-on article, more mechanistic, is titled: ¿Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), inhibit activation of nuclear factor NFkB by inhibiting both its nuclear localization and ability to bind DNA.¿

¿Our first paper,¿ Gutterman told BioWorld Today, ¿shows the pure avicin material, where we demonstrated that these compounds can induce apoptosis, cell death, and directly affect the mitochondria, with no increase in ROS ¿ reactive oxygen species. This article started with in vivo experiments, where we looked at the ability of avicin compounds to suppress carcinogenesis provoked by the chemical DMBA ¿ dimethylbenz[a]anthracine ¿ a component of tobacco smoke, followed by a tumor promoter. We shaved the backs of female mice, then daubed on the carcinogen solution, DMBA. We applied avicin topically on the shaved skin of the mice 15 minutes before the carcinogen, or the tumor promoter.¿

Reversing Cancerous Signs In Tumorous Mice

¿The upshot,¿ Gutterman recalled, ¿was that this in vivo experiment had a dramatic effect in suppressing the induction of hyperplasia ¿ that is, growth of tissue, inflammation, papillomas ¿ which are premalignant tumors. Then, we found that in the treated animals, there was a striking decrease in mutation of the tumor-promoting ras gene. One of the measurements of DNA damage,¿ he went on, ¿indicated that this was often caused by oxidative free radicals. And we noticed of course suppression of mutations as well as genetic instability ¿ that is, aneuploidy ¿ abnormal chromosomes.

¿In this study we definitely noticed a decrease in DNA damage, besides the tumor-promoting ras. So it appears there was an anti-inflammatory and anti-mutagenic effect caused by avicin. Because of these results, we started looking at some of the proinflammatory, precancerous cascades, which are clearly involved in inducing damage to DNA and lipids and so forth. And we focused first on NF-kB, as reported in the second paper.

¿There, we demonstrated that we inhibited NF-kB by a fairly unique mechanism. Most agents, like aspirin, suppress activation of NF-kB, and thereby, inflammation. In the case of the avicins, we appear to inhibit the binding directly of that nuclear factor.

¿So what we seem to have discovered here,¿ Gutterman observed, ¿is the natural substance that evolved in the acacia plant for its own ecological reasons. The plants clearly have evolved secondary metabolites that primarily can fend off predators like insects or microorganisms. We don¿t know yet, but I would speculate that since acacia is a nitrogen-fixing plant, it has to cope with stress-reducing responses in plants ¿ both oxidative and nitrogen stressing, as well as perhaps inducing cell death in certain predators, such as insects and microorganisms.¿

Plant molecular biologist Charles Arntzen, co-author of the two PNAS papers, is past president of the Boyce-Thompson Institute for Plant Research Inc. on the campus of Cornell University in Ithaca, N.Y. ¿When he got up there in 1995,¿ Gutterman recounted, ¿Arntzen discovered a collection of seeds from desert legumes in an affiliated arboretum. Knowing desert plants, he and I started a collaboration whereby extracts were made of the plants¿ metabolites. And I set up a very low-tech screen looking for their ability to induce cell death in a cell assay. We screened just a small number of compounds ¿ 100 or so ¿ and found this one extract that was able to kill cancer cells selectively.¿

Topical To Systemic, Mice To Man

¿The reason I got interested,¿ he observed, ¿was that desert plants, in my opinion, had not been looked at as extensively as rain-forest botanicals. What intrigued me was the fact that these plants clearly have to deal with a lot of ecological issues that the rain-forest plants don¿t have to cope with as much. For example, intense ultraviolet light. We have another paper where we demonstrated the suppression by avicin of UV damage in these mice.

¿So far, we¿ve been extracting avicin from the seed pods of A. victoriae, where it¿s a renewable source, coming out every year,¿ Gutterman continued. ¿We have established some root cultures of this, but right now we¿re getting a small number from the natural source on an annual basis from the pods, planted in a desert area of Arizona. Obtaining them from Australia is in process right now. We have not received any from there so far.¿

Turning to the eventuality of avicin in cancer therapy, he pointed out, ¿We know that there are a wide variety of premalignant malignancies that are characterized by inflammation. Such conditions, let alone others, could be important targets eventually for agents that suppress inflammation, and damage to DNA, as well as inducing apoptosis ¿ at least in some established cell lines.

¿As avicin has so far been applied topically, melanoma seems to be a candidate we can think about. But we have a lot of work to do in the pharmacology ¿ how to get avicin inside the body by systemic administration. I think that from what we know, we could likely be in patients with certain skin disorders within the next 12 to 18 months. Not systemic,¿ Gutterman concluded, ¿that will take longer.¿

Several patent applications have been filed covering avicin, and a company to license them is in the planning stages.