Amaryllidaceae Alkaloids Belonging to Different Structural Subgroups Display Activity against Apoptosis-Resistant Cancer Cells † Gwendoline Van Goietsenoven, ‡ Anna Andolfi, § Benjamin Lallemand, ⊥ Alessio Cimmino, § Delphine Lamoral-Theys, ⊥ Thierry Gras, ‡,⊥ Amina Abou-Donia, | Jacques Dubois, ⊥ Florence Lefranc, 3 Ve ´ronique Mathieu, ‡ Alexander Kornienko, ° Robert Kiss, ‡ and Antonio Evidente* ,§ Laboratoire de Toxicologie and Laboratoire de Chimie Analytique, Toxicologie et Chimie Physique Applique ´e, Institut de Pharmacie, UniVersite ´ Libre de Bruxelles, Brussels, Belgium, SerVice de Neurochirurgie, Ho ˆpiral Erasme, UniVersite ´ Libre de Bruxelles, Brussels, Belgium, Dipartimento di Scienze del Suolo, della Pianta, dell’Ambiente e delle Produzioni Animali, UniVersita ` di Napoli Federico II, Via UniVersita ` 100, 80055 Portici, Italy, Faculty of Pharmacy, UniVersity of Alexandria, Alexandria, Egypt, and Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801 ReceiVed December 18, 2009 Fifteen Amaryllidaceae alkaloids (1-15) were evaluated for their antiproliferative activities against six distinct cancer cell lines. Several of these natural products were found to have low micromolar antiproliferative potencies. The log P values of these compounds did not influence their observed activity. When active, the compounds displayed cytostatic, not cytotoxic activity, with the exception of pseudolycorine (3), which exhibited cytotoxic profiles. The active compounds showed similar efficacies toward cancer cells irrespective of whether the cell lines were responsive or resistant to proapoptotic stimuli. Altogether, the data from the present study revealed that lycorine (1), amarbellisine (6), haemanthamine (14), and haemanthidine (15) are potentially useful chemical scaffolds to generate further compounds to combat cancers associated with poor prognoses, especially those naturally resistant to apoptosis, such as glioblastoma, melanoma, non-small-cell lung, and metastatic cancers. Among various organisms that have been investigated in the search for small-molecule constituents with potential use in cancer treatment, plants of the family Amaryllidaceae have been particu- larly fruitful. 1,2 The therapeutic property of these plants was known already in the fourth century B.C.E., when Hippocrates of Cos used the oil from the daffodil, Narcissus poeticus L., for the treatment of uterine tumors. 2 In more recent times, more than 100 structurally diverse alkaloids, possessing a wide spectrum of biological activities, have been isolated from various Amaryllidaceae species. 3 Lycorine (1) was the first member of this family to be isolated in 1877. 2 Other examples of natural and synthetically derived compounds based on the pyrrolo[de]phenanthridine scaffold include amarbellisine (6) caranine (2), galanthine (4), pseudolycorine (3), norpluvine (5), and ungeremine (7). Another large alkaloid group from Amaryllidaceae is referred to as the lycorenine-type and is based on the [2]ben- zopyrano[3,4-g]indole skeleton, to which nobilisitine B (8) and clivonine (9, shown in hydrochloride form) belong, while tazettine (10) is the prototype representative of the pretazettine group. Alkaloids incorporating the 5,10-ethanophenanthridine skeleton belong to the crinine-type of compounds and include, for example, ambelline (11), buphanamine (12), buphanisine (13), haeman- thamine (14), and haemanthidine (15). Many of the Amaryllidaceae alkaloids exhibit antiproliferative properties, 2 and it has been proposed that these compounds are active in this regard by disrupting eukaryotic protein biosynthesis. 4-6 Close analogues of these alkaloids, some nonbasic isocarbostyrils from Amaryllidaceae species, have been shown recently to exhibit cytostatic activity and impair cancer cell proliferation and migration by disorganizing the actin cytoskeleton. 7,8 The isocarbostyrils, narciclasine 9 and pancratistatin, 10,11 induce apoptosis in cancer cells of epithelial origin (carcinoma), but not in glioma cells, 8 and only at high concentrations, i.e., one log higher than their in vitro growth- inhibitory IC 50 values. 9-11 This finding indicates clearly that induction of apoptosis is not the main route by which isocarbostyrils † Dedicated to the memory of Prof. Carlo Rosini. * Corresponding author. Tel: +39 081 253 9178. Fax: +39 081 253 9186. E-mail: evidente@unina.it. ‡ Laboratoire de Toxicologie, Universite ´ Libre de Bruxelles. ⊥ Laboratoire de Chimie Analytique, Toxicologie et Chimie Physique Applique ´e, Universite ´ Libre de Bruxelles. 3 Service de Neurochirurgie, Ho ˆpiral Erasme, Universite ´ Libre de Bruxelles. § Universita ` di Napoli Federico II. | University of Alexandria. ° New Mexico Institute of Mining and Technology. J. Nat. Prod. 2010, 73, 1223–1227 1223 10.1021/np9008255  2010 American Chemical Society and American Society of Pharmacognosy Published on Web 06/15/2010