Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia

Blood Cancer Journal

Volumn 4, Issue 11, 2014, Pages

  Chitta, K ^a   Paulus, A ^a   Caulfield, T R ^a   Akhtar, S ^a   Blake, M K K ^a   Ailawadhi, S ^a   Knight, J ^a   Heckman, M G ^a   Pinkerton, A ^b   Chanan Khan, A ^a  

^a MAYO CLINIC   (United States)

^b BURNHAM INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; AZADIRACHTIN; BORTEZOMIB; GEDUNIN; IBRUTINIB; IMMUNOGLOBULIN M; LIMONOID; NEEM LEAF EXTRACT; NIMBOLIDE; PLANT MEDICINAL PRODUCT; PROTEIN BCL 2; UNCLASSIFIED DRUG; BCL2 PROTEIN, HUMAN;

ANIMAL EXPERIMENT; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; CYTOTOXICITY; ENZYME LINKED IMMUNOSORBENT ASSAY; IC50; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; IN VIVO STUDY; JURKAT CELL LINE; MOLECULAR DOCKING; MOLECULAR MODEL; MOUSE; NONHUMAN; PROTEIN EXPRESSION; TUMOR GROWTH; TUMOR XENOGRAFT; WALDENSTROEM MACROGLOBULINEMIA; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; DRUG SCREENING; FEMALE; GENETICS; HUMAN; MALE; METABOLISM; NEOPLASMS, EXPERIMENTAL; PATHOLOGY; SCID MOUSE; TUMOR CELL LINE; WALDENSTROM MACROGLOBULINEMIA;

ANIMALS; APOPTOSIS; CELL LINE, TUMOR; FEMALE; HUMANS; JURKAT CELLS; LIMONINS; MALE; MICE; MICE, SCID; NEOPLASMS, EXPERIMENTAL; PROTO-ONCOGENE PROTEINS C-BCL-2; WALDENSTROM MACROGLOBULINEMIA; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84927949346     PISSN: None     EISSN: 20445385     Source Type: Journal    
DOI: 10.1038/bcj.2014.74     Document Type: Article

References (60)

1. Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 2003; 30: 110-115.
2. Ansell SM, Hodge LS, Secreto FJ, Manske M, Braggio E, Price-Troska T et al. Activation of TAK1 by MYD88 L265P drives malignant B-cell Growth in Non-Hodgkin lymphoma. Blood Cancer J 2014; 4: e183.
3. Paulus A, Chitta K, Akhtar S, Personett D, Miller KC, Thompson KJ et al. AT-101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenstrom macroglobulinaemia. Br J Haematol 2014; 164: 352-365.
4. Reed JC. Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 1997; 34: 9-19.
5. Thomas A, El Rouby S, Reed JC, Krajewski S, Silber R, Potmesil M et al. Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship between p53 gene mutation and bcl-2/bax proteins in drug resistance. Oncogene 1996; 12: 1055-1062.
6. Ailawadhi S, Miecznikowski J, Gaile DP, Wang D, Sher T, Mulligan G et al. Bortezomib mitigates adverse prognosis conferred by Bcl-2 overexpression in patients with relapsed/refractory multiple myeloma. Leuk Lymphoma 2012; 53: 1174-1182.
7. Iqbal J, Meyer PN, Smith LM, Johnson NA, Vose JM, Greiner TC et al. BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab. Clin Cancer Res 2011; 17: 7785-7795.
8. Ansell SM, Kyle RA, Reeder CB, Fonseca R, Mikhael JR, Morice WG et al. Diagnosis and management of Waldenstrom macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines. Mayo Clin Proc 2010; 85: 824-833.
9. Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 2012; 75: 311-335.
10. Balakrishnan K, Wierda WG, Keating MJ, Gandhi V. Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood 2008; 112: 1971-1980.
11. Shanafelt TD, Call TG, Zent CS, LaPlant B, Bowen DA, Roos M et al. Phase I trial of daily oral Polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia. J Clin Oncol 2009; 27: 3808-3814.
12. Paul R, Prasad M, Sah NK. Anticancer biology of Azadirachta indica L (neem): a mini review. Cancer Biol Ther 2011; 12: 467-476.
13. Chitta KS, Khan AN, Ersing N, Swaika A, Masood A, Paulus A et al. Neem leaf extract induces cell death by apoptosis and autophagy in B-chronic lymphocytic leukemia cells. Leuk Lymphoma 2013; 55: 652-661.
14. Harish Kumar G, Vidya Priyadarsini R, Vinothini G, Vidjaya Letchoumy P, Nagini S. The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis. Invest New Drugs 2010; 28: 392-401.
15. Raja Singh P, Arunkumar R, Sivakamasundari V, Sharmila G, Elumalai P, Suganthapriya E et al. Anti-proliferative and apoptosis inducing effect of nimbolide by altering molecules involved in apoptosis and IGF signalling via PI3K/Akt in prostate cancer (PC-3) cell line. Cell Biochem Funct 2013; 32: 217-228.
16. Karkare S, Chhipa RR, Anderson J, Liu X, Henry H, Gasilina A et al. Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth. Clin Cancer Res 2014; 20: 199-212.
17. Hart CP. Finding the target after screening the phenotype. Drug Discov Today 2005; 10: 513-519.
18. Kar S, Roy K. How far can virtual screening take us in drug discovery? Expert Opin Drug Discov 2013; 8: 245-261.
19. Wang L, Ma C, Wipf P, Liu H, Su W, Xie XQ. TargetHunter: an in silico target identification tool for predicting therapeutic potential of small organic molecules based on chemogenomic database. AAPS J 2013; 15: 395-406.
20. Grinter SZ, Liang Y, Huang SY, Hyder SM, Zou X. An inverse docking approach for identifying new potential anti-cancer targets. J Mol Graph Model 2011; 29: 795-799.
21. Chen YZ, Zhi DG. Ligand-protein inverse docking and its potential use in the computer search of protein targets of a small molecule. Proteins 2001; 43: 217-226.
22. Fan S, Geng Q, Pan Z, Li X, Tie L, Pan Y et al. Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol 2012; 6: 152.
23. Zheng R, Chen TS, Lu T. A comparative reverse docking strategy to identify potential antineoplastic targets of tea functional components and binding mode. Int J Mol Sci 2011; 12: 5200-5212.
24. Gao L, Fang JS, Bai XY, Zhou D, Wang YT, Liu AL et al. In silico target fishing for the potential targets and molecular mechanisms of baicalein as an antiparkinsonian agent: discovery of the protective effects on NMDA receptor-mediated neurotoxicity. Chem Biol Drug Des 2013; 81: 675-687.
25. Paulus A, Akhtar S, Kuranz M, Ailawadhi S, Miller K, Rivera CE et al. Development of a human IgM secreting model of Rpci-WM1 through xenografting In SCID mice for in vivo drug evaluation. Blood 2013; 122: 3081.
26. Chitta KS, Paulus A, Ailawadhi S, Foster BA, Moser MT, Starostik P et al. Development and characterization of a novel human Waldenstrom macroglobulinemia cell line: RPCI-WM1, Roswell Park Cancer Institute-Waldenstrom Macroglobulinemia 1. Leuk Lymphoma 2013; 54: 387-396.
27. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87: 99-163.
28. Zhang YJ, Caulfield T, Xu YF, Gendron TF, Hubbard J, Stetler C et al. The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation. Hum Mol Genet 2013; 22: 3112-3122.
29. Vivoli M, Caulfield TR, Martinez-Mayorga K, Johnson AT, Jiao GS, Lindberg I. Inhibition of prohormone convertases PC1/3 and PC2 by 2,5-dideoxystreptamine derivatives. Mol Pharmacol 2012; 81: 440-454.
30. Medina-Franco JL, Caulfield T. Advances in the computational development of DNA methyltransferase inhibitors. Drug Discov Today 2011; 16: 418-425.
31. Caulfield TR, Devkota B, Rollins GC. Examinations of tRNA Range of Motion Using Simulations of Cryo-EM Microscopy and X-Ray Data. J Biophys 2011; 2011: 219515.
32. Caulfield TR. Inter-ring rotation of apolipoprotein A-I protein monomers for the double-belt model using biased molecular dynamics. J Mol Graph Model 2011; 29: 1006-1014.
33. Caulfield T, Medina-Franco JL. Molecular dynamics simulations of human DNA methyltransferase 3B with selective inhibitor nanaomycin A. J Struct Biol 2011; 176: 185-191.
34. Caulfield T, Devkota B. Motion of transfer RNA from the A/T state into the A-site using docking and simulations. Proteins 2012; 80: 2489-2500.
35. Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013; 77: 639-646.
36. Abdul-Hay SO, Lane AL, Caulfield TR, Claussin C, Bertrand J, Masson A et al. Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity. J Med Chem 2013; 56: 2246-2255.
37. Hassan AA, Berthoux P, El Deeb S, Bonnevial L, Cecillon S, Berthoux F. Impact of hepatitis C on renal transplantation: a long-term study. Saudi J Kidney Dis Transpl 1999; 10: 487-492.
38. Bodduluru LN, Kasala ER, Thota N, Barua CC, Sistla R. Chemopreventive and therapeutic effects of nimbolide in cancer: The underlying mechanisms. Toxicol In Vitro 2014; 28: 1026-1035.
39. Nimmanapalli R, O'Bryan E, Kuhn D, Yamaguchi H, Wang HG, Bhalla KN. Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases. Blood 2003; 102: 269-275.
40. Banerjee Mustafi S, Chakraborty PK, Raha S. Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70. PLoS One 2010; 5: e8719.
41. Kloo B, Nagel D, Pfeifer M, Grau M, Duwel M, Vincendeau M et al. Critical role of PI3K signaling for NF-kappaB-dependent survival in a subset of activated B-celllike diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA 2011; 108: 272-277.
42. Gupta SC, Prasad S, Sethumadhavan DR, Nair MS, Mo YY, Aggarwal BB. Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment. Clin Cancer Res 2013; 19: 4465-4476.
43. Del Gaizo Moore V, Schlis KD, Sallan SE, Armstrong SA, Letai A. BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood 2008; 111: 2300-2309.
44. Priyadarsini RV, Manikandan P, Kumar GH, Nagini S. The neem limonoids azadirachtin and nimbolide inhibit hamster cheek pouch carcinogenesis by modulating xenobiotic-metabolizing enzymes, DNA damage, antioxidants, invasion and angiogenesis. Free Radic Res 2009; 43: 492-504.
45. Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Isobe S et al. Antiproliferative effect on human cancer cell lines after treatment with nimbolide extracted from an edible part of the neem tree (Azadirachta indica). Phytother Res 2007; 21: 245-250.
46. Cohen E, Quistad GB, Casida JE. Cytotoxicity of nimbolide, epoxyazadiradione and other limonoids from neem insecticide. Life Sci 1996; 58: 1075-1081.
47. Harish Kumar G, Chandra Mohan KV, Jagannadha Rao A, Nagini S. Nimbolide a limonoid from Azadirachta indica inhibits proliferation and induces apoptosis of human choriocarcinoma (BeWo) cells. Invest New Drugs 2009; 27: 246-252.
48. Priyadarsini RV, Murugan RS, Sripriya P, Karunagaran D, Nagini S. The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondriamediated apoptosis in human cervical cancer (HeLa) cells. Free Radic Res 2010; 44: 624-634.
49. Elumalai P, Gunadharini DN, Senthilkumar K, Banudevi S, Arunkumar R, Benson CS et al. Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway. Toxicol Lett 2012; 215: 131-142.
50. Wu Q, Kohli M, Bergen III HR, Cheville JC, Karnes RJ, Cao H et al. Preclinical evaluation of the supercritical extract of Azadirachta indica (neem) leaves in vitro and in vivo on inhibition of prostate cancer tumor growth. Mol Cancer Ther 2014; 13: 1067-1077.
51. Babykutty S, S PP, J NR, Kumar MA, Nair MS, Srinivas P et al. Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-kappaB in colon cancer cells. Mol Carcinog 2012; 51: 475-490.
52. Gupta SC, Prasad S, Reuter S, Kannappan R, Yadav VR, Ravindran J et al. Modification of cysteine 179 of IkappaBalpha kinase by nimbolide leads to downregulation of NF-kappaB-regulated cell survival and proliferative proteins and sensitization of tumor cells to chemotherapeutic agents. J Biol Chem 2010; 285: 35406-35417.
53. Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770-776.
54. Boswell EN, Chuma S, Banwait R, Hanlon C, Leblebjian H, Warren D et al. Phase I/II Trial Of Everolimus, Bortezomib and Rituximab in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia. Blood 2013; 122: 4402.
55. Tripsas CK, Yang G, Cao Y, Xu L, Hunter Z, Cropper SJ et al. A prospective multicenter study of the Bruton's Tyrosine Kinase inhibitor Ibrutinib in patients with relapsed or refractory Waldenstrom's macroglobulinemia. Blood 2013; 122: 251.
56. Gupta SC, Reuter S, Phromnoi K, Park B, Hema PS, Nair M et al. Nimbolide sensitizes human colon cancer cells to TRAIL through reactive oxygen species- and ERK-dependent up-regulation of death receptors, p53, and Bax. J Biol Chem 2011; 286: 1134-1146.
57. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10: 375-388.
58. Deng X, Gao F, Flagg T, May WS Jr. Mono- and multisite phosphorylation enhances Bcl2's antiapoptotic function and inhibition of cell cycle entry functions. Proc Natl Acad Sci USA 2004; 101: 153-158.
59. Perez-Galan P, Roue G, Lopez-Guerra M, Nguyen M, Villamor N, Montserrat E et al. BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. Leukemia 2008; 22: 1712-1720.
60. Glinsukon T, Somjaree R, Piyachaturawat P, Thebtaranonth Y. Acute toxicity of nimbolide and nimbic acid in mice, rats and hamsters. Toxicol Lett 1986; 30: 159-166.