Sabtu, 6 Julai 2013

Betulinic Acid Cancer Therapy Research

Betulinic Acid Cancer Therapy Research

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. 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.

In 1995, betulinic acid was reported as a selective inhibitor of human melanoma. Then it was demonstrated, that betulinic acid induces apoptosis in human melanoma in vitro and in vivo model systems. Currently it is undergoing development with assistance from the Rapid Access to Intervention in Development program of the National Cancer Institute. Also betulinic acid was found active against neuroectodermal (neuroblastoma, medulloblastoma, Ewing's sarcoma) and malignant brain tumors, ovarian carcinoma, in human leukemia HL-60 cells, malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines. 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.

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. 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. Betulinic acid induces apoptosis by direct effects on mitochondria, leading to cytochrome-c release, which in turn regulates the "downstream" caspase activation.

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. The suggestion is supported by study of Raisova (2001). On the other hand Rieber (1998) suggested that betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53. 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. Comparing the betulinic acid with other treatment modes, Zuco (2002) demonstrated that it was more than 10 times less potent than 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.

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. The effect of betulinic acid on melanoma cell lines is stronger than its growth-inhibitory effect on primary melanocytes. Study of combination of betulinic acid with ã-irradiation showed clearly additive effects, and indicates that they differ in their mode of action. Recently, Gauthier (2006) have synthesized a series of saponins of betulinic acid which demonstrated a strongly potent in vitro anticancer activity against human cancer cell lines.

Betulinic acid: a new chemotherapeutic agent in the treatment of neuroectodermal tumors.

S Fulda, I Jeremias, T Pietsch, KM Debatin
University Children's Hospital, Ulm, Germany.
We identified betulinic acid (BetA) as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing's sarcoma cells representing the most common solid tumors of childhood. BetA induced apoptosis independent of wild-type p53 protein and accumulation of death-inducing ligand/receptor systems such as CD95. BetA had a direct effect on mitochondria resulting in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-XL that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria conferred resistance to BetA at the level of mitochondrial dysfunction, protease activation and nuclear fragmentation. Neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis remained sensitive to treatment with BetA suggesting that BetA may bypass some forms of resistance. Moreover, BetA exhibited potent antitumor activity on primary tumor cell cultures from all neuroblastoma (4/4), all medulloblastoma (4/4) and most glioblastoma patients (20/24) ex vivo. These findings suggest that BetA may be a promising new agent in the treatment of neuroectodermal tumors in vivo.







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