Natural sesquiterpen alcohol a-bisabolol strongly induces apoptosis in glioma cell lines without affecting normal glial cell viability
E. Cavalieri1, S. Mariotto1, C. Fabrizi2, A. Carcereri de Prati1, R. Gottardo3, S. Leone2, L. V. Berra1, G. M. Lauro2, A. R. Ciampa1 , Hi. Suzuki1*
1
Department of Neuroscience and Vision, Section of Biochemistry, University of Verona
2
Department of Biology, University of Roma Tre, Italy,
3
Department of Medicine and Public health, Unit of Forensic medicine, University of Verona, Italy
Among human tumours, glioma is one of the most malignant ones and despite aggressive surgical resection and radiotherapy, the median survival in these patients does not normally exceed 1 year (1,4) The use of systemic chemotherapy may improve the efficacy of treatment, but its use is associated with significant toxicity and the long-term prognosis remains poor (2). Carmustine, one of the effective anti-glioma drug in the clinic, is, at concentration corresponding to LD10 (13 mg/kg), not able to kill completely glioma cells in vitro(5). Numerous compounds from plants have been reported to be potential anti-glioma agents, although major parts of these compounds sank into oblivion.. In the course of our research attempting to identify new natural compounds modulating inflammatory processes, we observed that a-bisabolol killed quickly a number of human transformed cell lines, including highly malignant glioma cell lines . a-bisabolol is a small oily sesquiterpene alcohol with molecuala massr. of 222.37 Daltons isolated from the essential oil of a variety of plants, shrubs and trees. Due to its no or very low toxicity in animals (LD50 = 13-14 g/kg, Merck Index), it is widely used in cosmetic preparations. However, only few scientific reports describing the biological effects of a-bisabolol are so far available in the literature (6,7). In the present study, we wanted to envisage in detail the cytotoxic effect and the type of death induced by a-bisabolol in glioma cells. For this purpose, we examined, as a human glioma cell model, T67 and U87 cell lines. As an animal model, we tested the rat glioma cell line C6.
At 2.5-3.5 mM the viability of these cells was reduced to 50 % with respect to untreated cells in 24 hours. Furthermore the same concentrations failed to affect the viability of normal rat astroglial cells, in line with its reported non-toxicity in rats (). At higher concentrations (10 mM) a-bisabolol killed completely the cells. Judging from caspase 3 activation, poly(ADP-ribose) polymerase cleavage, DNA ladder formation and hypo-G1 accumulation, the cytotoxicity triggered by a-bisabolol results from the induction of apoptosis. It is widely accepted that apoptosis is preferred to necrosis as a mechanism of tumour cell killing, since it does not induce inflammatory processes. Apoptosis is a physiological process which is characterised by the formation of apoptotic bodies inside cells and seems to be genetically programmed. Tumour cells may be resistant to apoptosis, presumably due to defects in apoptosis pathways. Two major routes, extrinsic and intrinsic, have been identified through which cytotoxic drugs induce apoptosis. The first one is mediated by death receptors. In the second pathway, mitochondria play essential roles.
The dissipation of mitochondrial-inner transmembrane potential and the release of cytochrome c from mitochondria indicate that apoptosis occurs through the intrinsic pathway. Taken together, these results point out that a-bisabolol may be considered a novel compound able to inhibit glioma cell growth and survival.
References
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[5] M.L. Rosenblum, M.A. Gerosa, D.V. Dougherty, C.B. Wilson, Improved treatment of a brain-tumor model, J. Neurosurg. 58 (1983) 177-182.
[6] A. Hernandez-Ceruelos, E. Madrigal-Bujaidar, C. De La Cruz, Inhibitory effect of chamomile essential oil on the sister chromatid exchanges induced by daunorubicin and methyl methanesulfonate in mouse bone marrow, Toxicol. Lett. 135 (2002) 103-110.
[7] L.F. Villegas, A. Marcalo, J. Martin, I.D. Fernandez, H. Maldonado, A.J. Vaisberg, G.B. Hammond, (+)-epi-Alpha-bisabolol [correction of bisabolol] is the wound-healing principle of Peperomia galioides: investigation of the in vivo wound-healing activity of related terpenoids, J Nat Prod. 64 (2001) 1357-1359.
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