Cytotoxic and Apoptosis-Inducing Activities of Limonoids from the Seeds of Azadirachta indica (Neem)

Abstract

Thirty-five limonoids, including 15 of the azadiradione type (1-15), five of the gedunin type (16-20), four of the azadirachtin type (21-24), nine of the nimbin type (25-33), and two degraded limonoids (34, 35), isolated from Azadirachta indica seed extracts, were evaluated for their cytotoxic activities against five human cancer cell lines. Seven compounds (3, 6, 7, 16, 18, 28, and 29) exhibited cytotoxic activity against one or more cell lines. Among these compounds, 7-deacetyl-7-benzoylepoxyazadiradione (7), 7-deacetyl-7-benzoylgeduin (18), and 28-deoxonimbolide (28) exhibited potent cytotoxic activity against HL60 leukemia cells with IC(50) values in the range 2.7-3.1 μM. Compounds 7, 18, and 28 induced early apoptosis in HL60 cells, observed by flow cytometry. Western blot analysis showed that compounds 7, 18, and 28 activated caspases-3, -8, and -9 in HL60 cells. This suggested that compounds 7, 18, and 28 induced apoptotic cell death in HL60 cells via both the mitochondrial- and the death receptor-mediated pathways. Futhermore, compound 7 was shown to possess high selective cytotoxicity for leukemia cells since it exhibited only weak cytotoxicity against a normal lymphocyte cell line (RPMI 1788).

3,5‐Dimethylorsellinic Acid Derived Meroterpenoids from Eupenicillium sp. 6A‐9, a Fungus Isolated from the Marine Sponge Plakortis simplex

“…[44] Doxorubicin (IC 50 = 0.25, 0.16, 0.44, and 0.04 μM, respectively) was used as the positive control.…”

New triterpenoids from the kernels of Azadirachta indica

“…Juss., as one of the most popular pesticidal plant and traditional Indian medicine, was distributed throughout Asia, Africa, and other tropical parts of the world. [2][3][4] During the past four decades, more than 200 compounds, including terpenoids, 1 flavones, 5 steroids, 6 coumarins 7 and polysaccharides 8 had been isolated from different parts of A. indica, and some of them showed the significant bioactivities such as insecticides, 1,9,10 antifungal, 1,3 antitumor 1,2,11,12 and antimalarial. 1,13,14 Azadirachtin, as a well known natural pesticide, 3,15 was always extracted from the kernels of A. indica.…”

“…With the aim of searching for natural compounds with biological activities, we have investigated the kernels (after extracting azadirachtin) of A. indica collected from Mangshi Bright Neem Industry Developments Ltd., Yunnan Province of China. As a result, four new triterpenoids (1)(2)(3)(4), along with three known constituents (5-7), were isolated from the dried kernels of A. indica.…”

Stimulation of Erythrocyte Cell Membrane Scrambling by Gedunin

“…The substance has thus been considered for the treatment of malignancy [3,4,6,7]. Mechanisms invoked in the triggering of tumor cell apoptosis following gedunin treatment include inhibition of the antiapoptotic protein HSP90 and downregulation of the anti-apoptotic proteins HSP70 and HSP27 [3], activation of the caspases 3, 8, and 9 [8] and inhibition of sphingomyelin biosynthesis [9]. Gedunin has further been shown to be effective in vitro against Plasmodium falciparum [10,11,12,13,14].…”