Betulinic Acid for cancer treatment and prevention

Abstract

Betulinic acid is a natural product with a range of biological effects, for example potent antitumor activity. This anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window. Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinic acid hold great promise as a novel therapeutic strategy in the treatment of human cancers.

Keywords: AIF, apoptosis inducing factor; Apaf-1, Apoptotic protease activating factor-1; BA, betulinic acid; DIABLO, direct IAP Binding protein with Low PI; HtrA2, high temperature requirement protein A; IAPs, Inhibitor of Apoptosis Proteins; MOMP, mitochondrial outer membrane permeabilization; PARP, Poly (ADP-ribose) Polymerase; ROS, reactive oxygen species; Smac, second mitochondria-derived activator of caspase; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; apoptosis; betulinic acid; cancer; mitochondria; zVAD.fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone.

Figure 1.

Structure of betulinic acid.

Figure 2.

Apoptosis pathways. Apoptosis pathways can be initiated at the level of the mitochondria by the release of apoptogenic factors such as cytochrome c, Smac or AIF from the mitochondrial intermembrane space into the cytosol (mitochondrial or intrinsic pathway) [51]. Smac promotes apoptosis by neutralizing “Inhibitor of Apoptosis Proteins” (IAP)-mediated inhibition of caspase-3 and -9 [51]. Alternatively, apoptosis can be triggered by ligation of death receptors (DR) such as CD95 or TRAIL receptors by their cognate ligands, i.e. CD95 ligand or TRAIL (receptor or extrinsic pathway) [52]. Death receptor stimulation in turn leads to receptor trimerization, recruitment of adaptor molecules such as FADD and activation of the initiator caspase-8, which propagates the death signal to effector caspases such as caspase-3 [–54]. The BH3 domain only protein Bid links the receptor to the mitochondrial pathway [15]: Bid is activated by caspase-8-mediated cleavage and translocates to mitochondria to promote cytochrome c release. Apoptosis can be inhibited by at various levels, e.g. by FLIP, Bcl-2 or IAPs [15, 55, 56].