Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis

Abstract

As a result of bioassay-guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma.

Differentiation-inducing activity of lupane triterpenes on a mouse melanoma cell line

“…Other pentacyclic triterpenes such as oleanane and ursane could not differentiate B16 2F2 cells. Previously, it was reported that compound 10 was a selective anticancer agent against some human cancer cell lines (Fulda et al 1999;Pisha et al 1995;Schmidt et al 1997), and the carboxyl group at the C-17 was essential for apoptotic activities (Lee et al 1998). In our studies of anti-proliferative effects by these triterpenes on B16 2F2 cells, compounds 8-12, all of which have a carbonyl group at C-17, were found to inhibit B16 2F2 cell proliferation at lower concentrations than other compounds.…”

Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani

“…20 The activity found with 16 against intracellular Leishmania, without substantial toxicity for host cells, points to the interest of carrying out further tests of this compound on animal models. The mechanism of action of betulin and betulin derivatives has been only partially explored (it prevents DNA cleavage and the formation of topoisomerase-DNA complex), 18,[27][28][29] and internalization by Leishmania is unknown. It is interesting to note that the most active derivative exhibited a higher inhibitory activity against amastigotes than against promastigotes.…”

Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice

“…with saline (0.1 ml), BA (10 mg kg À1 day À1 ), VCR (0.065 mg kg À1 day À1 ) or a combination of both drugs (BA, 10 mg kg À1 day À1 ; VCR, 0.065 mg kg À1 day À1 ) (Figure 1). The dose of BA for the treatment of mice was decided by referring to a previous report (Pisha et al, 1995). Body weights of mice were recorded every 4 days to determine whether the treatment influenced health status.…”

“…Betulinic acid (BA), a pentacyclic triterpene isolated from the root bark of Morus australis or Clerodendrum mandarinorum and many other medicinal plants (Zhu et al, 1996;Ko et al, 1997), has recently been reported to have cytotoxic activity against several tumour cell lines (Pisha et al, 1995;Fulda et al, 1997Fulda et al, , 1998Wick et al, 1999;Kwon et al, 2002;Wachsberger et al, 2002). Betulinic acid is a novel experimental antineoplastic agent for human melanoma cells in vitro (Pisha et al, 1995;Wachsberger et al, 2002).…”

“…Betulinic acid is a novel experimental antineoplastic agent for human melanoma cells in vitro (Pisha et al, 1995;Wachsberger et al, 2002). Betulinic acid also induces apoptosis in neuroectodermal tumour and glioma cells (Fulda et al, 1997(Fulda et al, , 1998Wick et al, 1999).…”