buylotrogold

Is anybody around who knows something about the toxicology of betulinic acid?

Here are a few references. Betulinic acid is an interesting triterpene derivative, and it appears that there is some controversy regarding its mechanism(s) of inducing cytotoxicity. Best of results, Chuck Bioorg Med Chem Lett 1998 Jul 7;8(13):1707-12 Synthesis of betulinic acid derivatives with activity against human melanoma. Kim DS, Pezzuto JM, Pisha E Department of Medicinal Chemistry and Pharmacognosy (m/c 833), College of Pharmacy, University of Illinois at Chicago 60612-7231, USA. [Medline record in process] Betulinic acid has been modified at C-3, C-20, and C-28 positions and the toxicity of the derivatives has been evaluated against cultured human melanoma (MEL-2) and human epidermoid carcinoma of the mouth (K cell lines. This preliminary investigation demonstrates that simple modifications of the parent structure of betulinic acid can produce potentially important derivatives, which may be developed as antitumor drugs. PMID: 9873420, UI: 99090106 Cancer Res 1998 Dec 15;58(24):5876-7 Correspondence re: S. Fulda et al., Betulinic acid triggers CD95 (Apo1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res., 57: 4956-4964, 1997. Rieber M, Rieber MS [Medline record in process] PMID: 9865749, UI: 99081347 J Biol Chem 1998 Dec 18;273(51):33942-8 Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. Fulda S, Scaffidi C, Susin SA, Krammer PH, Kroemer G, Peter ME, Debatin KM University Children's Hospital, Prittwitzstrasse 43, D-89075 Ulm, Germany. [Medline record in process] Different classes of anticancer drugs may trigger apoptosis by acting on different subcellular targets and by activating distinct signaling pathways. Here, we report that betulinic acid (BetA) is a prototype cytotoxic agent that triggers apoptosis by a direct effect on mitochondria. In isolated mitochondria, BetA directly induces loss of transmembrane potential independent of a benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone-inhibitable caspase. This is inhibited by bongkrekic acid, an agent that stabilizes the permeability transition pore complex. Mitochondria undergoing BetA-induced permeability transition mediate cleavage of caspase-8 (FLICE/MACH/Mch5) and caspase-3 (CPP32/Yama) in a cell-free system. Soluble factors such as cytochrome c or apoptosis-inducing factor released from BetA-treated mitochondria are sufficient for cleavage of caspases and nuclear fragmentation. Addition of cytochrome c to cytosolic extracts results in cleavage of caspase-3, but not of caspase-8. However, supernatants of mitochondria, which have undergone permeability transition, and partially purified apoptosis-inducing factor activate both caspase-8 and caspase-3 in cytosolic extracts and suffice to activate recombinant caspase-8. These findings show that induction of mitochondrial permeability transition alone is sufficient to trigger the full apoptosis program and that some cytotoxic drugs such as BetA may induce apoptosis via a direct effect on mitochondria. PMID: 9852046, UI: 99069377 J Nat Prod 1998 Nov;61(11):1343-7 Preparation and cytotoxic effect of ceanothic acid derivatives. Lee SS, Chen WC, Huang CF, Su Y School of Pharmacy, College of Medicine, National Taiwan University, and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, Republic of China. [Medline record in process] Six ceanothane and 1-norceanothane derivatives (1, 2, 8-11) were prepared from ceanothic acid dibenzyl ester. These ring-A homologues of betulinic acid exhibited cytotoxic effects. Among these, 1-decarboxy-3-oxo-ceanothic acid (2) was found to be the most cytotoxic against OVCAR-3 and HeLa cancer cell lines, with an IC50 of 2.8 and 6.6 &mgr;g/mL, respectively, and an IC50 of 11.3 &mgr;g/mL against normal cell line FS-5. PMID: 9834149, UI: 99055021 Planta Med 1998 Oct;64(7):655-7 Betulinic acid inhibits aminopeptidase N activity. Melzig MF, Bormann H The triterpene betulinic acid inhibits the activity of aminopeptidase N (EC 3.4.11.2) in a dose-dependent manner. An IC50 of 7.3 +/- 1.4 microM was determined for betulinic acid. This inhibitory activity is higher than that of bestatin' (IC50 = 16.9 +/- 4.1 microM), a well known inhibitor of this enzyme. The finding supports the idea that betulinic acid acts as anti-melanoma agent via inhibition of aminopeptidase N activity. Publication Types:     a.. Letter PMID: 9810272, UI: 99027967 Cancer Res 1998 Oct 1;58(19):4453-60 Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Fulda S, Susin SA, Kroemer G, Debatin KM University Children's Hospital, Ulm, Germany. Apoptosis mediated by anticancer drugs may involve activation of death-inducing ligand/receptor systems such as CD95 (APO-1/Fas), cleavage of caspases, and perturbance of mitochondrial functions. We investigated the sequence of these events in SHEP neuroblastoma cells transfected with Bcl-2 or Bcl-X(L) using two different drugs, namely, doxorubicin (Doxo), which activates the CD95/CD95 ligand (CD95-L) system, and betulinic acid (Bet A), which does not enhance the _expression_ of CD95 or CD95-L and which, as shown here, directly targets mitochondria. Apoptosis induced by both drugs was inhibited by Bcl-2 or Bcl-X(L) over_expression_ or by bongkrekic acid, an agent that stabilizes mitochondrial membrane barrier function, suggesting a critical role for mitochondria. After Doxo treatment, enhanced CD95/CD95-L _expression_ and caspase-8 activation were not blocked by Bcl-2 or Bcl-X(L) and were found in cells with a mitochondrial transmembrane potential (delta psi(m)) that was still normal (delta psi(m)high cells). In marked contrast, after Bet A treatment, caspase-8 activation occurred in a Bcl-2- or Bcl-X(L)-inhibitable fashion and was confined to cells that had lost their delta psi(m) (delta psi(m)low cells). Mitochondria from cells treated with either Doxo or Bet A induced cleavage of both caspase-8 and caspase-3 in cytosolic extracts. Thus, caspase-8 activation may occur upstream or downstream of mitochondria, depending on the apoptosis-initiating stimulus. In contrast to caspase-8, cleavage of caspase-3 or poly(ADP-ribose)polymerase was always restricted to delta psi(m)low cells, downstream of the Bcl-2- or Bcl-X(L)-controlled checkpoint of apoptosis. Cytochrome c, released from mitochondria undergoing permeability transition, activated caspase-3 but not caspase-8 in a cell-free system. However, both caspases were activated by apoptosis-inducing factor, indicating that the mechanism of caspase-8 activation differed from that of caspase-3 activation. Taken together, our findings demonstrate that perturbance of mitochondrial function constitutes a central coordinating event in drug-induced cell death. PMID: 9766678, UI: 98438068 DNA Cell Biol 1998 May;17(5):399-406 Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human _meta_static melanoma. Rieber M, Strasberg Rieber M IVIC, Tumor Cell Biology Laboratory, Caracas, Venezuela. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it Because betulinic acid was recently described as a melanoma-specific inducer of apoptosis, we investigated whether this agent was comparably effective against _meta_static tumors and those in which _meta_static ability and 92-kD gelatinase activity had been decreased by introduction of a normal chromosome 6. Human _meta_static C8161 melanoma cells showed greater DNA fragmentation and growth arrest and earlier loss of viability in response to betulinic acid than their non-_meta_static C8161/neo 6.3 counterpart. These effects involved induction of p53 without activation of p21WAF1 and were synergized by bromodeoxyuridine in _meta_static Mel Juso, with no comparable responses in non-_meta_static Mel Juso/neo 6 cells. Our data suggest that betulinic acid exerts its inhibitory effect partly by increasing p53 without a comparable effect on p21WAF1. PMID: 9628583, UI: 98290547 Bioorg Med Chem 1997 Dec;5(12):2133-43 Anti-AIDS agents