Dr. Řádek

It is a tree wide-spread in many areas. Couple of species has been used - T. impetiginosa, T. serratifolia, T. avellanedae. Especially bark has been used.
The bark contains especially phenolic-, iridoid-, phenylethanoid-, lignan- and isocoumarin glycosides, naphtochinones (lapachole and its cyclic derivative beta-lapachone) and cyclopentenic dialdehydes.1,2,3,4,5,6
Therapeutic usage is very general. Many studies investigating extracts or isolated substances effects on growth and metabolism of some tumour cells. A study from year 2002 has investigated influence of beta-lapachone on human multiple myeloma cells. Beta-lapachone showed significant cytotoxic effect on multiple myeloma cells, peripher mononuclear cells and bone marrow stroma cells were resistent relatively. The measures showed that interleukine 6 didn´t protect multiple myeloma cells before beta-lapachone induced apoptosis. Beta-lapachone reduced multiple myeloma cells proliferation, too.7
Next study from year 2005 has shown that tumour cells (FsaII cells of C3H mice were used) are more sensitive on beta-lapachone activity if they were exposed to radiation before beta-lapachone usage. The radiation evoked long-term increase of NAD(P)H chinon oxidoreductase activity, and tumour cells sensitivity was dependent on the enzyme activity. When beta-lapachon was used first and the cells were exposed to radiation after beta-lapachone usage, the effect wasn´t so expressive. The combination of radiation and follow-up beta-lapachone treatment was more effective.8 A study published in May 2006 came to the same results, human prostate cancer cells were used.9
Beta-lapachone effect mechanism on prostate carcinoma cells growth inhibition has been investigated in a study from year 2003. It was found that cell proliferation inhibition is caused by apoptosis induction (it was confirmed by observation of morphological modifications and proteinolysis of poly-ADP-ribose-polymerase) and stopping of cell cycle progression in G1 phase (confirmed with cytometric analysis). The effect was attached to retinoblastome protein (pRB) phosphorylation decrease and binding increase. Beta-lapachone decreased cyclin-dependent kinases (Cdks) and cyclin-E-asociated kinase activities without their expression modification.10 Similar mechanism – apoptosis induction, poly-ADP-ribose-polymerasis level decrease and influence on other proteins – has been observed in another study from year 2003, HCT-116 colon tumour cells have been used for this study.11
Effect of beta-lapachone on prostate carcinoma cells has been studied again in year 2005. The apoptosis induction caused by beta-lapachon was confirmed, than it was found that beta-lapachon decreases cyclooxygenase-2-mRNA levels and protein expression, but doesn´t affect cyclooxygenase 1 levels. This estimate related to prostaglandine E2 synthesis decrease. Beta-lapachon inhibited telomerase activity dose dependently. Human telomerase reverse transcriptase expression was decreased.12 The same mechanism was observed in lung carcinoma cells.13
Well known is an antibacterial effect of bark or extracts respectively. One study from year 2006 has investigated antibacterial activity of substances isolated from bark against Helicobacter pylori. Their effect was compared to standard drugs – amoxicilin, metronidazole and tetracycline. Isolated substances were determined by spectroscopic analysis - 2-(hydroxymethyl)anthrachinone, anthrachinon-2-carboxylic acid and 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naftochinone (lapachol). The strongest activity against H. pylori showed 2-(hydroxymethyl)anthrachinone, other substances were less effective.14
Next study investigated antibacterial activity of beta-lapachone, 3-hydroxy-beta-N-lapachone and alpha-lapachone against methicilin resistent Staphylococcus aureus, Staphylococcus epidermidis a Staphylococcus haemolyticus. Antibacterial activity, but no bactericid effect was observed.15
Very interesting study has been made in year 2005. Activity of anthrachinon-2-carboxylic acid and lapachol against 10 human enteric bacteria was investigated. As a standard drugs chloramphenicol and tetracycline were used. Anthrachinon-2-carboxylic acid showed very strong inhibition activity against Clostridium paraputrificum (1 microg/disc). Less activity was observed against Escherichia coli and Clostridium perfringens (100 microg/disc, both substances). No influence on Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium infantis, Lactobacilus acidophilus and Lactobacilus casei was observed. Important function for antibacterial activity has the methyl group on C-2 position of 1,4 naphtochinone derivatives probably.16

Sources:
1. Warashina, T., Nagatani, Y., Noro, T.: Constituents from the bark of Tabebuia impetiginosa. Chem. Pharm. Bull., 2006, 54(1), s.14-20.
2. Awale, S., Kawakami, T., Tezuka, Y., Ueda, J.Y., Tanaka, K., Kadota, S.: Nitric oxide (NO) production inhibitory constituents of Tabebuia avellanedae from Brazil. Chem. Pharm.Bull.,2005,53(6),s.710-3.
3. Warashina, T., Nagatani, Y., Noro, T.: Further constituents from the bark of Tabebuia impetiginosa.Phytochemistry,2005,66(5),s.589-97.
4. Warashina, T., Nagatani, Y., Noro, T.: Constituents from the bark of Tabebuia impetiginosa.Phytochemistry,2004,65(13),s.2003-11.
5. Pinto, C.N., Dantas, A.P., De Moura, K.C., Emery, F.S., Polequevitch, P.F., Pinto, M.C., de Castro, S.L., Pinto, A.V.: Chemical reactivity studies with naphthoquinones from Tabebuia with anti-trypanosomal efficacy. Arzneimittelforschung, 2000, 50(12),s.1120-8.
6. Koyamaa,J., Moritaa, I., Tagaharaa, K., Hiraib, K.: Cyclopentene dialdehydes from Tabebuia impetiginosa. Phytochemistry, 2000, 53, (8), s. 869-872.
7. Gupta, D., Podar, K., Tai, Y., Lin, B., Hideshima, T., Akiyama, M., LeBlanc, R., Catley, L., Mitsiades, N., Mitsiades, C., Chauhan, D., Munshi, N.C., Anderson, K.C.: β-lapachone, a novel plant product, overcomes drug resistance in human multiple myeloma cells. Experimental Hematology, 2002, 30, (7), s 711-20.
8. Park, H.J., Ahn, K.J., Ahn, S.D., Choi, E.,Sang Wook Lee, S.W., Williams, B., Kim, E.J., Griffin, R., Bey, E.A., Bornmann, W.G.,Gao, J., Park, H.J.,Boothman, D.A., Song, Ch.W.: Susceptibility of cancer cells to β-lapachone is enhanced by ionizing radiation . International Journal of Radiation Oncology,Biology,Physics, 2005, 61 (1),s 212-9.
9. Suzuki, M., Amano, M., Choi, J., Park, H.J., Williams, B.W., Ono, K., Song, C.W.: Synergistic effects of radiation and beta-lapachone in DU-145 human prostate cancer cells in vitro. Radiat. Res., 2006, 165(5), s.525-31.
10. Choi, Y.H., Kang, H.S., Yoo, M.A.: Suppression of human prostate cancer cell growth by beta-lapachone via down-regulation of pRB phosphorylation and induction of Cdk inhibitor p21(WAF1/CIP1). J. Biochem. Mol. Biol., 2003, 36(2), s.223-9.
11. Choi, B.T., Cheong, J., Choi, Y.H.: beta-Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-kappaB in human colon cancer HCT-116 cells. Anticancer Drugs., 2003, 14(10), s.845-50.
12. Lee, J.H., Cheong, J., Park, Y.M., Choi, Y.H.: Down-regulation of cyclooxygenase-2 and telomerase activity by beta-lapachone in human prostate carcinoma cells. Pharmacol. Res., 2005, 51(6), s.553-60.
13. Woo, H.J., Choi, Y.H.: Growth inhibition of A549 human lung carcinoma cells by beta-lapachone through induction of apoptosis and inhibition of telomerase activity. Int. J. Oncol., 2005,26(4), s. 1017-23.
14. Park, B.S., Lee, H.K., Lee, S.E., Piao, X.L., Takeoka, G.R., Wong, R.Y., Ahn, Y.J., Kim, J.H.: Antibacterial activity of Tabebuia impetiginosa Martius ex DC (Taheebo) against Helicobacter pylori. J. Ethnopharmacol., 2006, 105(1-2), s.255-62.
15. Pereira, E.M., Machado, T.de B., Leal, I.C., Jesus, D.M., Damaso, C.R., Pinto, A.V., Giambiagi-deMarval, M., Kuster, R.M., Santos, K.R.: Tabebuia avellanedae naphthoquinones: activity against methicillin-resistant staphylococcal strains, cytotoxic activity and in vivo dermal irritability analysis. Ann. Clin. Microbiol. Antimicrob., 2006, 22(5), s.5.
16. Park, B.S., Kim, J.R., Lee, S.E., Kim, K.S., Takeoka, G.R., Ahn, Y.J., Kim, J.H.: Selective growth-inhibiting effects of compounds identified in Tabebuia impetiginosa inner bark on human intestinal bacteria. J. Agric. Food. Chem., 2005, 53(4), s.1152-7.

Mgr. Katerina Horackova