Betulinic acid

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Betulinic acid is a naturally occurring triterpene originally extracted from the bark of an African tree, Ziziphus mauritiana lam (Rhamnaceae) possesses anti-HIV, anti-malarial, and anti-inflammatory properties [1]. It was later found in the bark of the common white birch. Unlike some other natural product anti-tumor agents (e. g. taxol), sourcing is not a problem because betulin is a major component of the bark of the white birch tree and this can readily be converted to betulinic acid [2]. Also it was isolated from various plants as Trifillum peltatum, Ancistocladuis heyeneaus, Diospyros leucomelas, Tetracera boliviana, Sizigium formosanum [3], Chaenomeles sinensis [4], Pulsatilla chinensis [5].

In 1995, betulinic acid was reported as a selective inhibitor of human melanoma. [2]. Then it was demonstrated, that betulinic acid induces apoptosis in human melanoma in vitro and in vivo model systems [6]. Currently it is undergoing development with assistance from the Rapid Access to Intervention in Development program of the National Cancer Institute. [2] Also betulinic acid was found active against neuroectodermal (neuroblastoma, medulloblastoma, Ewing's sarcoma [7]) and malignant brain tumors [3, 8], ovarian carcinoma [3], in human leukemia HL-60 cells [5], malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines [9]. In contrast, epithelial tumors, such as breast carcinoma, colon carcinoma, small cell lung carcinoma and renal cell carcinoma as well as T-cell leukemia cells were completely refractory to treatment with betulinic acid [7]. Regarding the mode of action of betulinic acid little is known about its antiproliferative and apoptosis-inducing mechanisms. In neuroectodermal tumor cells betulinic acid –induced apoptosis is accompanied by caspase activation, mitochondrial membrane alterations and DNA fragmentation [7, 9]. Caspases are produced as inactive proenzymes, which are proteolytically processed to their active forms. These proteases can cooperate in proteolytic cascades, in which caspases activate themselves and each other. The initiation of the caspases cascade may lead to the activation of endonucleases like caspase-activated DNAase (CAD). After activation CAD contributes to DNA degradation [9]. Betulinic acid induces apoptosis by direct effects on mitochondria, leading to cytochrome-c release, which in turn regulates the "downstream" caspase activation [9]. Betulinic acid bypasses resistance to CD95 and doxorubicin-mediated apoptosis, due to different molecular mechanism of betulinic acid-induced apoptosis. Controversial is a role of p53 in betulinic acid-induced apoptosis. Fulda (1997) suggested p53-independent mechanism of the apoptosis, basing on fact of no accumulation of wild-type p53 detected upon treatment with the betulinic acid, whereas wild-type p53 protein strongly increased after treatment with Doxorubicin [7]. The suggestion is supported by study of Raisova (2001) [10]. On the other hand Rieber (1998) suggested that betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53 [11]. The study also demonstrated preferential apoptotic effect of betulinic acid on C8161 metastatic melanoma cells, with greater DNA fragmentation and growth arrest and earlier loss of viability than their non-metastatic C8161/neo 6.3 counterpart [11]. Comparing the betulinic acid with other treatment modes, Zuco (2002) demonstrated that it was more than 10 times less potent than doxorubicin (IC50 4.5 μg/ml Vs IC50 0.21-034 μg/ml in doxorubicin) and showed an in vitro antiproliferative activity against melanoma and non-melanoma cell lines, including those resistant to doxorubicin. On the human normal dermatoblast cell line betulinic acid was 2-5 times less toxic than doxorubicin [3]. The ability of betulinic acid to induce two different effects (cytotoxic and cytostatic) on two clones derived from the same human melanoma metastasis suggests that the development of clones resistant to this agent will be more unlikely, than that to conventional cytotoxic drugs. Moreover in spite of the lower potency compared with doxorubicin betulinic acid seems to be selective for tumor cells with minimal toxicity against normal cells. [3] The effect of betulinic acid on melanoma cell lines is stronger than its growth-inhibitory effect on primary melanocytes [12]. Study of combination of betulinic acid with γ-irradiation showed clearly additive effects, and indicates that they differ in their mode of action [12]. Recently, Gauthier et al. have synthesized a serie of saponins of betulinic acid who demonstrated a strongly potent in vitro anticancer activity against human cancer cell lines [13].

[edit] References

1. Chowdhury AR, Mandal S, Mittra B, Sharma S, Mukhopadhyay S, Majumder HK. Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives. Med Sci Monit. 2002 Jul; 8(7): BR254-65.

2. Tan Y, Yu R, Pezzuto JM. Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin Cancer Res. 2003 Jul; 9(7): 2866-75.

3. Zuco V, Supino R, Righetti SC, Cleris L, Marchesi E, Gambacorti-Passerini C, Formelli F. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells.Cancer Lett. 2002 Jan 10; 175(1): 17-25.

4. Gao H, Wu L, Kuroyanagi M, Harada K, Kawahara N, Nakane T, Umehara K, Hirasawa A, Nakamura Y. Antitumor-promoting constituents from Chaenomeles sinensis KOEHNE and their activities in JB6 mouse epidermal cells. Chem Pharm Bull (Tokyo). 2003 Nov; 51(11): 1318-21.

5. Ji ZN, Ye WC, Liu GG, Hsiao WL. 23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells. Life Sci. 2002 Nov 22; 72(1): 1-9.

6. Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM. Betulinic acid induces apoptosis in human neuroblastoma cell lines. Eur J Cancer. 1997 Oct; 33(12):2007-10.

7. Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M, Nunez G, Krammer PH, Peter ME, Debatin KM. Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res. 1997 Nov 1; 57(21): 4956-64.

8. Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M. Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing.J Pharmacol Exp Ther. 1999 Jun; 289(3): 1306-12.

9. Thurnher D, Turhani D, Pelzmann M, Wannemacher B, Knerer B, Formanek M, Wacheck V, Selzer E. Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. Head Neck. 2003 Sep; 25(9): 732-40.

10. Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE, Geilen CC. The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol. 2001 Aug; 117(2): 333-40

11. Rieber M, Strasberg Rieber M. Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma. DNA Cell Biol. 1998 May; 17(5): 399-406.

12. Selzer E, Pimentel E, Wacheck V, Schlegel W, Pehamberger H, Jansen B, Kodym R. Effects of betulinic acid alone and in combination with irradiation in human melanoma cells. J Invest Dermatol. 2000 May; 114(5): 935-40.

13. Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A. Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents. Bioorg. Med. Chem. 2006 May: 14, 6713-6725.