ReviewPost ScreenTargeting mitochondrial apoptosis by betulinic acid in human cancers
Introduction
Natural products have been used to combat human diseases for thousands of years [1] and play an increasing role in drug discovery and development. In fact, the majority of anticancer and anti-infectious agents are of natural origin. The antitumor activity of natural products has been explained, at least in part, by their ability to trigger cell death pathways, including apoptosis in cancer cells. Apoptosis or programmed cell death is the cell's intrinsic death program that plays a pivotal role in maintaining tissue homeostasis and that is highly conserved among different animal species [2]. Because apoptosis is involved in the regulation of many physiological processes, defective apoptosis signaling may contribute to a variety of different pathological conditions. Thus, increased apoptosis is involved in degenerative processes affecting neurons, muscle or lymphoid tissues. Conversely, disabled apoptosis is one of the hallmarks of human cancer cells [3]. Thus, cancer cells have a marked tendency to disable the mitochondrial (intrinsic) pathway of apoptosis. Besides their vital function for cellular bioenergetics, mitochondria play a key role in the regulation of the point-of-no-return during apoptosis. Betulinic acid (BA) is a natural product that exhibits potent antitumor activities and that triggers the mitochondrial path to apoptosis [4]. Here we review the current literature on the mitochondrion-targeted actions of BA and discuss the perspective to take advantage of BA to overcome some forms of anticancer drug resistance [4].
Section snippets
BA, a phytochemical with antitumor activity
BA (3β, hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpenoid of the lupane class that belongs to the group of terpenes 5, 6. BA is contained in various plants throughout the plant kingdom and, hence, throughout the world (Fig. 1a) [7]. For example, considerable amounts of BA are available in the outer bark of several tree species, including white-barked birch trees. It is interesting to note that betulin (3β-lup-20(29)-en-3,28-diol), the reduced congener of BA, was one of the first
The mitochondrial pathway of apoptosis
Apoptosis is an intrinsic cell death program that is operative in every cell and regulated by defined signaling pathways [10]. Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic or mitotic), the permeabilization of mitochondrial membranes is frequently the decisive event that delimits the frontier between survival and death. The intrinsic (mitochondrial) pathway of apoptosis is triggered upon treatment with chemotherapeutic agents or
Mechanisms of action of BA
Numerous studies over the past few years have been aimed at elucidating the molecular mechanisms of BA-mediated antitumor activity. One characteristic feature of BAs cytotoxicity is its ability to trigger the mitochondrial pathway of apoptosis in cancer cells (Fig. 2).
Additional anticancer effects of BA
BA has been reported to exert antiangiogenic effects by inhibiting growth factor-induced in vitro angiogenesis in endothelial cells [33]. Interestingly, the antiangiogenic activity of BA was linked to its mitochondrial damaging effects [33]. Accordingly, the inhibition of mitochondrial permeability transition by pharmacological inhibitors attenuated the antiangiogenic activity of BA on endothelial cells [33]. Further, the activation of selective proteasome-dependent degradation of the
Anticancer activity of BA
The antitumor cytotoxicity of BA has been extensively studied in a panel of cancer cell lines, primary tumor samples and xenograft mouse models. While initial reports suggested that BA is selectively cytotoxic against melanoma cell lines [9], anticancer activity was subsequently reported against other types of human malignancies, including neuroblastoma, glioblastoma, medulloblastoma, Ewing tumor, leukemia as well as several carcinomas, that is head and neck, colon, breast, liver, lung,
Other biological activities of BA
As with many natural products, BA exhibits a plethora of biological activities besides its anticancer properties. Probably the most important biological effect of BA, apart from its cytotoxicity against cancer cells, is its anti-HIV-1 activity 7, 60, 61, 62. Although its mechanism of action has not been fully determined, it has been shown that some BA analogs disrupt viral fusion to the cell in a postbinding step through interaction with the viral glycoprotein gp41, whereas other BA analogs
Conclusions
The natural compound BA shows potent anticancer activity through activation of the mitochondrial pathway of apoptosis in cancer cells. BA may also be used in combination protocols to enhance its antitumor activity, for example with chemo- or radiotherapy or with the death receptor ligand TRAIL. Because of its relative selective cytotoxicity against malignant compared to normal cells, BA is a promising new experimental anticancer agent for the treatment of human cancers.
Acknowledgements
This work has been supported by a joint project of Deutscher Akademischer Auslandsdienst (DAAD) and Institut National du Cancer (INCa). Simone Fulda is supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Forschung und Technologie, Wilhelm-Sander-Stiftung, Else-Kröner-Fresenius Stiftung, the European Community (ApopTrain, APO-SYS) and IAP6/18; Guido Kroemer by grants from Ligue contre le Cancer (laboratoire labelliseé), Institut
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