| Glioblastoma Treatments: Supplements: Asiatic acid |
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Asiatic acid
Summary Asiatic acid is an ancient, traditional herbal extract derived from the plant Centella asiatica. Its historical uses as an adaptogenic tonic are well known to herbalists, and recent studies show that it is also highly cytotoxic to many cancer cell lines in vitro, including the U-87MG glioblastoma line. Asiatic acid may also have anti-angiogenesis properties. In addition, topical preparations have been shown to have unique wound-healing properties which may benefit brain tumor patients in their recovery from surgeries. Moreover, the low risk of adverse side-effects, the long history of successful use in traditional medicine, the substantial evidence that it crosses the blood brain barrier, and the relatively recent evidence that it is cytotoxic to many cancer cell lines, suggests that asiatic acid might be an appropriate complementary supplement to comprehensive brain tumor treatment. Discussion Asiatic acid is one of the constituent triterpenes found in the plant Centella asiatica, commonly called Gotu Kola. This ancient herb is known in both traditional Chinese medicine ("Luei Gong Gen") and Indian Ayurvedic medicine ("Mandookaparni"), and entered the French pharmacopoeia in 1884. In a unique study published in 2006(1), the Biomaterials Science and Engineering Laboratory at the Massachusetts Institute of Technology (MIT) found that asiatic acid caused dose- and time-dependent cell death in a common glioblastoma cell line, U-87MG. This cell death occurs via apoptosis, Ca2+-mediated necrotic cell death, and activation of caspase-9 and caspase-3. Another mechanism modulated by asiatic acid may be nitric oxide (NO) synthesis. In one study of its effects in treating gastric ulcers, asiatic acid was found to have anti-inflammatory and healing effects due to inhibition of NO synthesis(4). The biology of NO in solid tumors is not completely clear, but appears to be important, and seemingly conflicting studies exist. A New York University Medical Center study in 1992 found evidence that the nitric oxide generating donor molecules S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) inhibited cerebellar glial cell proliferation without cytotoxicity(13). Studies at other institutions in 1999 (12) and 2003 (8) confirmed this conclusion in the context of gliomas. However, a 2003 Japanese study by Oyoshi, et al, reported that malignant glioma cells produce twice as much NO when compared to normal cells, yet the level produced is still about 40 times less than the NO levels produced in vitro in the studies which showed proliferation suppression(5). To further explain the complex interactions of NO within cells, a 2005 study from Univ. of Pittsburgh found that NO can be either cytoprotective or cytotoxic to epithelial liver cells (hepatocytes) depending on conditions within the cell. The Pittsburgh team showed that glutathione concentrations could largely dictate these conditions; the combination of glutathione depletion and NO donor molecules caused a significant increase in cytotoxicity. Oyoshi noted that several studies have reported gliomas to express high levels of inducible nitric oxide synthase (iNOS), the enzyme that produces NO, while another in vivo study showed that high nitric oxide synthase-expressing tumors are also known to be highly vascularized. Perhaps not coincidentally, several studies, including two in September, 2007, have reported evidence that iNOS upregulates VEGF expression(6,7). Thus, Oyoshi suggests that intratumoral NO production is insufficient to prevent proliferation and may, in fact, have the opposite effect through upregulation of VEGF, a known angiogensis growth factor. So, despite the fact that artificially high levels of NO inhibits glioma proliferation in vitro, intratumoral NO production is implicated in neovascularization and appears to be an important target for future chemotherapies. A dozen or more other studies have also shown asiatic acid to be cytotoxic in a wide variety of cancer cell lines, ranging from breast cancer to melanoma to myeloma(2). It also has been reported to exhibit a cytotoxic effect against Hep G2 cells via Ca2+ release and p53 upregulation(10). While evidence that asiatic acid can cross the blood brain barrier in humans is mostly inferred from its effects, a 2007 study in India demonstrated that asiatic acid readily crosses the blood brain barrier in rats(3). Given the clear evidence of neurological effects, the evidence that asiatic acid crosses the blood brain barrier in humans as well is strong. Perhaps only genistein and curcumin match asiatic acid in their sheer number of potential therapeutic uses. The ailments traditionally treated by Centella asiatica extract in Chinese and Indian medicine are numerous, including heart disease, high blood pressure, rheumatism, fevers, nervous disorders, bronchitis, asthma, syphilis, and a whole host a skin conditions caused by leprosy, lupus, varicose ulcers, eczema, and psoriasis. In Chinese medicine, gotu kola is considered a miracle elixir of sorts, providing an elevated sense of well-being when taken internally and soothing wounds and skin when used externally. Furthermore, asiatic acid has been found to prevent UVA-mediated photoaging, to inhibit amyloid-induced neurotoxicity, and to possess antiulcer and antihepatofibric activities (Jew et al., 2000; Lee et al., 2000; Soo Lee et al., 2003; Dong et al., 2004). A US patent was filed in 2007 for the use of asiatic acid in the treatment of pulmonary fibrosis. A Thai study in 2000 also found that one of the constituents of Centella asiatica, asiaticoside (a glycoside of asiatic acid), inhibited the common herpes simplex viruses (HSV-1 and HSV-2). For brain tumor patients, the benefits of asiatic acid are many as well. Among the scientifically-validated effects which could be used by brain tumor patients, asiatic acid provides:
In a multicenter, double-blind placebo-controlled study in 1987, a "significant improvement" in edema of the lower limbs was observed(11). Interestingly, if asiatic acid crosses the blood brain barrier and inhibits VEGF and/or reduces inflammation, it may also help reduce peritumoral edema, however this highly speculative hypothesis must be confirmed scientifically. Furthermore, this study also reported that asiatic acid improved venous distensibility (the ability of veins to adjust to increased pressure) in legs. As a result, it is believed that asiatic acid has mild blood pressure lowering properties. The wound healing properties of asiatic acid have been explored in great detail throughout scientific journals, and the primary mechanisms are collagen production stimulation and anti-inflammatory properties. Asiatic acid has been found to prevent scars, and several patents and a few products have already surfaced taking advantage of this fact. It has been studied in helping patients treat chronic wounds from surgery and cutaneous ulcers. For the wound healing properties, asiatic acid can be used topically or orally, and there are even studies which have injected it intramuscularly with great success. Madecassol is the brand name of a product produced from the titrated extract of Centella asiatica, containing asiaticoside, asiatic acid and madecassic acid in 4:3:3 ratio. In a 1990 French study, the product was found to increase collagen synthesis in a dose-dependent fashion. The asiatic acid component of the product was found to be the only component responsible for the collagen synthesis stimulation(9). It is important to note that quantitative analysis of the constituents of Centella asiatica samples from various countries within its endemic habitat has revealed that the asiatic acid content of the extract varies dramatically based on geographic region in which the plant was harvested. Centella asiatica from Madagascar has been found to contain the highest levels of asiatic acid. To date, the only known Centella asiatica supplement manufacturer to explicitly state the country of origin as Madagascar is SolaRay. The toxicity profile for asiatic acid appears to be very good, with no known adverse side-effects at recommended dosages. Dosage limits remain largely unexplored with dose-escalation studies, however one small study from Argentina in 2005 suspected Centella asiatica extract in 3 cases of non-fatal liver toxicity. As with all herbal extracts, dosing should begin slowly to avoid allergies and individual sensitivities, and then proceed to the recommended levels. According to the Sloan Kettering web site, hyperglycemia and sedation have occurred at high doses, but it does not give the doses it is referring to. Other anecdotal adverse side-effects collected from non-scientific sources include contact dermatitis, headache, and decreased fertility in women trying to get pregnant. Extracts from Centella asiatica contain a wide variety of chemicals, making it impossible to establish a primary means of metabolism in humans. There appears to be no known drug/substance interactions found in the literature. Fortunately, however, a 1990 study discusses the pharmacokinetics of relatively low doses of Centella asiatica in a small group of healthy volunteers(12). Gotu Kola should not be confused with the kola nut (Cola nitida), which is known for its high caffeine concentration. Gotu Kola contains no caffeine. Asiatic acid is extremely promising for brain tumor patients, and needs more attention by Western researchers to confirm and further explore the wide variety of beneficial effects reported by Asian researchers. References 1. C. W. Cho, D. S. Choi, M. H. Cardone, C. W. Kim, A. J. Sinskey, C. Rha. 2. Hsu YL, Kuo PL, Lin LT, Lin CC. 3. Ramanathan M, Sivakumar S, Anandvijayakumar PR, Saravanababu C, Pandian PR. 4. Guo JS, Cheng CL, Koo MW. 5. Oyoshi T, Nomoto M, Hirano H, Kuratsu J. 6. Shigyo H, Nonaka S, Katada A, Bandoh N, Ogino T, Katayama A, Takahara M, Hayashi T, Harabuchi Y. 7. Singh RP, Agarwal R. 8. Viani P, Giussani P, Brioschi L, Bassi R, Anelli V, Tettamanti G, Riboni L. 9. Maquart FX, Bellon G, Gillery P, Wegrowski Y, Borel JP. 10. Lee YS, Jin DQ, Kwon EJ, Park SH, Lee ES, Jeong TC, Nam DH, Huh K, Kim JA. 11. Pointel JP, Boccalon H, Cloarec M, Ledevehat C, Joubert M. 11. Grimaldi R, De Ponti F, D'Angelo L, Caravaggi M, Guidi G, Lecchini S, Frigo GM, Crema A. 12. Kurimoto M, Endo S, Hirashima Y, Hamada H, Ogiichi T, Takaku A. 13. Garg UC, Devi L, Turndorf H, Goldfrank LR, Bansinath M. |
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