Summary
Natural products discovered from medicinal plants have played an important role in the treatment of cancer. In an effort to identify novel small molecules which can affect the proliferation of lymphoma cells, we tested methyl angolensate (MA), a plant derived tetranortriterpenoid, purified from the crude extract of the root callus of Soymida febrifuga commonly known as Indian red wood tree. We have tested MA for its cytotoxic properties on Burkitt’s lymphoma cell lines, using various cellular assays. We observed that MA induces cytotoxicity in Daudi cells in a dose-dependent manner using trypan blue, MTT and LDH assays. We find that the treatment with MA led to activation of DNA double-strand break repair proteins including KU70 and KU80, suggesting the activation of nonhomologous DNA end joining pathway in surviving cells. Further, we find that methyl angolensate could induce apoptosis by cell cycle analysis, annexin V-FITC staining, DNA fragmentation and PARP cleavage. Besides, MA treatment led to reactive oxygen species generation and loss of mitochondrial transmembrane potential. These results suggest the activation of mitochondrial pathway of apoptosis. Hence, we identify MA as a potential chemotherapeutic agent against Daudi cells.
Similar content being viewed by others
References
Rowley JD (2001) Chromosome translocations: dangerous liaisons revisited. Nat Rev Cancer 1:245–250
Nambiar M, Kari V, Raghavan SC (2008) Chromosomal translocations in cancer. Biochim Biophys Acta 1786(2):139–152
Devesa SS, Fears T (1992) Non-Hodgkin’s lymphoma time trends: United States and international data. Cancer Res 52(19 Suppl):5432s–5440s
Raghavan SC, Lieber MR (2006) DNA structures at chromosomal translocation sites. Bioessays 28(5):480–494
Lieber MR, Yu K, Raghavan SC (2006) Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair (Amst) 5(9–10):1234–1245
Lieber MR (1993) in The Causes and Consequences of Chromosomal Translocations. Kirsch I (ed). CRC Press, p 239–275
Emmanouilides C, Jazirehi AR, Bonavida B (2002) Rituximab-mediated sensitization of B-non-Hodgkin’s lymphoma (NHL) to cytotoxicity induced by paclitaxel, gemcitabine, and vinorelbine. Cancer Biother Radiopharm 17(6):621–630
Cline JM, Hughes CL Jr (1998) Phytochemicals for the prevention of breast and endometrial cancer. Cancer Treat Res 94:107–134
Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7(5):357–369
Place AE et al (2003) The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clin Cancer Res 9(7):2798–2806
Chiruvella KK et al (2008) Methyl angolensate, a natural tetranortriterpenoid induces intrinsic apoptotic pathway in leukemic cells. FEBS Lett 582(29):4066–4076
Orisadipe A et al (2001) Spasmolytic activity of methyl angolensate: a triterpenoid isolated from Entandrophragma angolense. Biol Pharm Bull 24(4):364–367
Penido C et al (2006) Inhibition of allergen-induced eosinophil recruitment by natural tetranortriterpenoids is mediated by the suppression of IL-5, CCL11/eotaxin and NFkappaB activation. Int Immunopharmacol 6(2):109–121
Abdelgaleil SA, Hashinaga F, Nakatani M (2005) Antifungal activity of limonoids from Khaya ivorensis. Pest Manag Sci 61(2):186–190
Chiruvella KK et al (2007) Phytochemical and antimicrobial studies of methyl angolensate and luteolin-7-O-glucoside isolated from callus cultures of soymida febrifuga. Int J Biomed Sci 3:269–278
Gowda NR et al (2009) Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents. Bioorg Med Chem Lett 19(16):4594–4600
Korzeniewski C, Callewaert DM (1983) An enzyme-release assay for natural cytotoxicity. J Immunol Methods 64(3):313–320
Kavitha CV et al (2009) Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells. Biochem Pharmacol 77(3):348–363
Shahabuddin MS et al (2009) A novel DNA intercalator, butylamino-pyrimido[4′,5′:4,5]selenolo(2,3-b)quinoline, induces cell cycle arrest and apoptosis in leukemic cells. Invest New Drugs
Li ZX et al (2009) Curcumin induces apoptosis and inhibits growth of human Burkitt’s lymphoma in xenograft mouse model. Mol Cells 27(3):283–289
Frankfurt OS, Krishan A (2003) Apoptosis-based drug screening and detection of selective toxicity to cancer cells. Anticancer Drugs 14(7):555–561
Castrillo A et al (2001) Inhibition of the nuclear factor kappa B (NF-kappa B) pathway by tetracyclic kaurene diterpenes in macrophages. Specific effects on NF-kappa B-inducing kinase activity and on the coordinate activation of ERK and p38 MAPK. J Biol Chem 276(19):15854–15860
Lee JH et al (2002) Kaurane diterpene, kamebakaurin, inhibits NF-kappa B by directly targeting the DNA-binding activity of p50 and blocks the expression of antiapoptotic NF-kappa B target genes. J Biol Chem 277(21):18411–18420
Pulvertaft JV (1964) Cytology of Burkitt’s Tumour (African Lymphoma). Lancet 1(7327):238–240
Lin YJ et al (2009) Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells. Biochem Biophys Res Commun 378(4):683–688
Liu LF et al (2004) Action of solamargine on human lung cancer cells–enhancement of the susceptibility of cancer cells to TNFs. FEBS Lett 577(1–2):67–74
Reyes FJ et al (2006) (2Alpha, 3beta)-2, 3-dihydroxyolean-12-en-28-oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells. FEBS Lett 580(27):6302–6310
Roy HK et al (2001) Polyethylene glycol induces apoptosis in HT-29 cells: potential mechanism for chemoprevention of colon cancer. FEBS Lett 496(2–3):143–146
Michaelis M et al (2010) Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem Pharmacol 79(2):130–136
Kumar A et al (2008) Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by a new series of substituted-1, 3, 4-oxadiazole derivatives. Invest New Drugs 26(5):425–435
Kim SY et al (2007) Surfactin from Bacillus subtilis displays anti-proliferative effect via apoptosis induction, cell cycle arrest and survival signaling suppression. FEBS Lett 581(5):865–871
Dassonneville L et al (2000) Cytotoxicity and cell cycle effects of the plant alkaloids cryptolepine and neocryptolepine: relation to drug-induced apoptosis. Eur J Pharmacol 409(1):9–18
Koopman G et al (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84(5):1415–1420
Tan ML et al (2005) Methanolic extract of Pereskia bleo (Kunth) DC. (Cactaceae) induces apoptosis in breast carcinoma, T47-D cell line. J Ethnopharmacol 96(1–2):287–294
Chung YM, Bae YS, Lee SY (2003) Molecular ordering of ROS production, mitochondrial changes, and caspase activation during sodium salicylate-induced apoptosis. Free Radic Biol Med 34(4):434–442
Ikai T et al (2006) Magnolol-induced apoptosis is mediated via the intrinsic pathway with release of AIF from mitochondria in U937 cells. Biol Pharm Bull 29(12):2498–2501
Ohguchi K et al (2005) Vaticanol C-induced cell death is associated with inhibition of pro-survival signaling in HL60 human leukemia cell line. Biosci Biotechnol Biochem 69(2):353–356
Nakagawa Y et al (2005) A potent apoptosis-inducing activity of a sesquiterpene lactone, arucanolide, in HL60 cells: a crucial role of apoptosis-inducing factor. J Pharmacol Sci 97(2):242–252
Deriano L et al (2005) Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway. Blood 105(12):4776–4783
Acknowledgements
We thank Dr. Bibha Choudhary, Dr. Rama Gopal Ghanta, Dr. Omana Joy, and Ms. Mridula Nambiar, and other members of SCR laboratory for their help and suggestions. This work was supported by Lady Tata Memorial Trust international award for leukemia research (London) for SCR. KKC is supported by DBT postdoctoral fellowship from India.
Conflict of interest
Authors disclose that there is no conflict of interests.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(PDF 136 kb)
Rights and permissions
About this article
Cite this article
Chiruvella, K.K., Raghavan, S.C. A natural compound, methyl angolensate, induces mitochondrial pathway of apoptosis in Daudi cells. Invest New Drugs 29, 583–592 (2011). https://doi.org/10.1007/s10637-010-9393-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-010-9393-7