Top

BMC Cancer

Published in:

Open Access 01-12-2013 | Research article

N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma

Authors: Shanique K E Edwards, Carissa R Moore, Yan Liu, Sukhdeep Grewal, Lori R Covey, Ping Xie

Published in: BMC Cancer | Issue 1/2013

Abstract

Background

TRAF3, a new tumor suppressor identified in human non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), induces PKCδ nuclear translocation in B cells. The present study aimed to evaluate the therapeutic potential of two PKCδ activators, N-Benzyladriamycin-14-valerate (AD 198) and ingenol-3-angelate (PEP005), on NHL and MM.

Methods

In vitro anti-tumor activities of AD 198 and PEP005 were determined using TRAF3^-/- mouse B lymphoma and human patient-derived MM cell lines as model systems. In vivo therapeutic effects of AD 198 were assessed using NOD SCID mice transplanted with TRAF3^-/- mouse B lymphoma cells. Biochemical studies were performed to investigate signaling mechanisms induced by AD 198 or PEP005, including subcellular translocation of PKCδ.

Results

We found that AD 198 exhibited potent in vitro and in vivo anti-tumor activity on TRAF3^-/- tumor B cells, while PEP005 displayed contradictory anti- or pro-tumor activities on different cell lines. Detailed mechanistic investigation revealed that AD 198 did not affect PKCδ nuclear translocation, but strikingly suppressed c-Myc expression and inhibited the phosphorylation of ERK, p38 and JNK in TRAF3^-/- tumor B cells. In contrast, PEP005 activated multiple signaling pathways in these cells, including PKCδ, PKCα, PKCϵ, NF-κB1, ERK, JNK, and Akt. Additionally, AD198 also potently inhibited the proliferation/survival and suppressed c-Myc expression in TRAF3-sufficient mouse and human B lymphoma cell lines. Furthermore, we found that reconstitution of c-Myc expression conferred partial resistance to the anti-proliferative/apoptosis-inducing effects of AD198 in human MM cells.

Conclusions

AD 198 and PEP005 have differential effects on malignant B cells through distinct biochemical mechanisms. Our findings uncovered a novel, PKCδ-independent mechanism of the anti-tumor effects of AD 198, and suggest that AD 198 has therapeutic potential for the treatment of NHL and MM involving TRAF3 inactivation or c-Myc up-regulation.

Available only for authorised users

Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS: Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006, 107: 265-276. 10.1182/blood-2005-06-2508.CrossRefPubMedPubMedCentral

Ruddon R: The epidemiology of human cancer. Cancer biology. Edited by: Ruddon RW. 2007, New York, USA: Oxford University Press, 62-116. 4

Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A, et al: SEER cancer statistics review, 1975–2006. Surveillance, epidemiology, and end results (SEER) program. 2008, Bethesda, MD: National Cancer Institute, Public-Use, http://www.seer.cancer.gov

Xie P, Stunz LL, Larison KD, Yang B, Bishop GA: Tumor necrosis factor receptor-associated factor 3 is a critical regulator of B cell homeostasis in secondary lymphoid organs. Immunity. 2007, 27: 253-267. 10.1016/j.immuni.2007.07.012.CrossRefPubMedPubMedCentral

Gardam S, Sierro F, Basten A, Mackay F, Brink R: TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity. 2008, 28: 391-401. 10.1016/j.immuni.2008.01.009.CrossRefPubMed

Nagel I, Bug S, Tonnies H, Ammerpohl O, Richter J, Vater I, Callet-Bauchu E, Calasanz MJ, Martinez-Climent JA, Bastard C, et al: Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del(14)(q24.1q32.33). Leukemia. 2009, 23: 2153-2155. 10.1038/leu.2009.149.CrossRefPubMed

Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, et al: Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007, 12: 131-144. 10.1016/j.ccr.2007.07.003.CrossRefPubMedPubMedCentral

Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, et al: Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007, 12: 115-130. 10.1016/j.ccr.2007.07.004.CrossRefPubMedPubMedCentral

Braggio E, Keats JJ, Leleu X, Van Wier S, Jimenez-Zepeda VH, Valdez R, Schop RF, Price-Troska T, Henderson K, Sacco A, et al: Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemia. Cancer Res. 2009, 69: 3579-3588. 10.1158/0008-5472.CAN-08-3701.CrossRefPubMedPubMedCentral

10.

Xie P, Kraus ZJ, Stunz LL, Bishop GA: Roles of TRAF molecules in B lymphocyte function. Cytokine Growth Factor Rev. 2008, 19: 199-207. 10.1016/j.cytogfr.2008.04.002.CrossRefPubMedPubMedCentral

11.

Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O’Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, et al: DUBA: a deubiquitinase that regulates type I interferon production. Science. 2007, 318: 1628-1632. 10.1126/science.1145918.CrossRefPubMed

12.

Bishop GA, Xie P: Multiple roles of TRAF3 signaling in lymphocyte function. Immunol Res. 2007, 39: 22-32. 10.1007/s12026-007-0068-1.CrossRefPubMed

13.

Xu Y, Cheng G, Baltimore D: Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity. 1996, 5: 407-415. 10.1016/S1074-7613(00)80497-5.CrossRefPubMed

14.

Moore CR, Liu Y, Shao CS, Covey LR, Morse HC, Xie P: Specific deletion of TRAF3 in B lymphocytes leads to B lymphoma development in mice. Leukemia. 2012, 26: 1122-1127. 10.1038/leu.2011.309.CrossRefPubMed

15.

Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y, Abe M, Tsukiyama T, Nagahama H, Ohno S, Hatakeyama S, et al: Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta. Nature. 2002, 416: 865-869. 10.1038/416865a.CrossRefPubMed

16.

Mecklenbrauker I, Saijo K, Zheng NY, Leitges M, Tarakhovsky A: Protein kinase Cdelta controls self-antigen-induced B-cell tolerance. Nature. 2002, 416: 860-865. 10.1038/416860a.CrossRefPubMed

17.

Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL: Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999, 190: 1697-1710. 10.1084/jem.190.11.1697.CrossRefPubMedPubMedCentral

18.

Zhang B, Wang Z, Li T, Tsitsikov EN, Ding HF: NF-kappaB2 mutation targets TRAF1 to induce lymphomagenesis. Blood. 2007, 110: 743-751. 10.1182/blood-2006-11-058446.CrossRefPubMedPubMedCentral

19.

Mecklenbrauker I, Kalled SL, Leitges M, Mackay F, Tarakhovsky A: Regulation of B-cell survival by BAFF-dependent PKCdelta-mediated nuclear signalling. Nature. 2004, 431: 456-461. 10.1038/nature02955.CrossRefPubMed

20.

Lothstein L, Savranskaya L, Barrett CM, Israel M, Sweatman TW: N-benzyladriamycin-14-valerate (AD 198) activates protein kinase C-delta holoenzyme to trigger mitochondrial depolarization and cytochrome c release independently of permeability transition pore opening and Ca2+ influx. Anticancer Drugs. 2006, 17: 495-502. 10.1097/00001813-200606000-00002.CrossRefPubMed

21.

Lothstein L, Savranskaya L, Sweatman TW: N-Benzyladriamycin-14-valerate (AD 198) cytotoxicty circumvents Bcr-Abl anti-apoptotic signaling in human leukemia cells and also potentiates imatinib cytotoxicity. Leuk Res. 2007, 31: 1085-1095. 10.1016/j.leukres.2006.11.003.CrossRefPubMed

22.

Diaz Bessone MI, Berardi DE, Campodonico PB, Todaro LB, Lothstein L, de Kier Joffe ED B, Urtreger AJ: Involvement of PKC delta (PKCdelta) in the resistance against different doxorubicin analogs. Breast Cancer Res Treat. 2011, 126: 577-587. 10.1007/s10549-010-0956-2.CrossRefPubMed

23.

Hampson P, Chahal H, Khanim F, Hayden R, Mulder A, Assi LK, Bunce CM, Lord JM: PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood. 2005, 106: 1362-1368. 10.1182/blood-2004-10-4117.CrossRefPubMed

24.

Serova M, Ghoul A, Benhadji KA, Faivre S, Le Tourneau C, Cvitkovic E, Lokiec F, Lord J, Ogbourne SM, Calvo F, et al: Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol Cancer Ther. 2008, 7: 915-922. 10.1158/1535-7163.MCT-07-2060.CrossRefPubMed

25.

Hampson P, Wang K, Milverton L, Ersvaer E, Bruserud O, Lord JM: Kinetics of ERK1/2 activation determine sensitivity of acute myeloid leukaemia cells to the induction of apoptosis by the novel small molecule ingenol 3-angelate (PEP005). Apoptosis. 2010, 15: 946-955. 10.1007/s10495-010-0507-7.CrossRefPubMed

26.

van de Loosdrecht AA, Beelen RH, Ossenkoppele GJ, Broekhoven MG, Langenhuijsen MM: A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. J Immunol Methods. 1994, 174: 311-320. 10.1016/0022-1759(94)90034-5.CrossRefPubMed

27.

Ghoul A, Serova M, Astorgues-Xerri L, Bieche I, Bousquet G, Varna M, Vidaud M, Phillips E, Weill S, Benhadji KA, et al: Epithelial-to-mesenchymal transition and resistance to ingenol 3-angelate, a novel protein kinase C modulator, in colon cancer cells. Cancer Res. 2009, 69: 4260-4269. 10.1158/0008-5472.CAN-08-2837.CrossRefPubMed

28.

Xie P, Kraus ZJ, Stunz LL, Liu Y, Bishop GA: TNF receptor-associated factor 3 is required for T cell-mediated immunity and TCR/CD28 signaling. J Immunol. 2011, 186: 143-155. 10.4049/jimmunol.1000290.CrossRefPubMed

29.

Morse HC, Anver MR, Fredrickson TN, Haines DC, Harris AW, Harris NL, Jaffe ES, Kogan SC, MacLennan IC, Pattengale PK, et al: Bethesda proposals for classification of lymphoid neoplasms in mice. Blood. 2002, 100: 246-258. 10.1182/blood.V100.1.246.CrossRefPubMed

30.

Xie P, Bishop GA: Roles of TNF receptor-associated factor 3 in signaling to B lymphocytes by carboxyl-terminal activating regions 1 and 2 of the EBV-encoded oncoprotein latent membrane protein 1. J Immunol. 2004, 173: 5546-5555.CrossRefPubMed

31.

Zhou S, Kurt-Jones EA, Cerny AM, Chan M, Bronson RT, Finberg RW: MyD88 intrinsically regulates CD4 T-cell responses. J Virol. 2009, 83: 1625-1634. 10.1128/JVI.01770-08.CrossRefPubMed

32.

Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D, Naldini L: A third-generation lentivirus vector with a conditional packaging system. J Virol. 1998, 72: 8463-8471.PubMedPubMedCentral

33.

Cai C, Lothstein L, Morrison RR, Hofmann PA: Protection from doxorubicin-induced cardiomyopathy using the modified anthracycline N-benzyladriamycin-14-valerate (AD 198). J Pharmacol Exp Ther. 2010, 335: 223-230. 10.1124/jpet.110.167965.CrossRefPubMedPubMedCentral

34.

Sweatman TW, Seshadri R, Israel M: Pharmacology of N-benzyladriamycin-14-valerate in the rat. Cancer Chemother Pharmacol. 1999, 43: 419-426. 10.1007/s002800050917.CrossRefPubMed

35.

Hofmann PA, Israel M, Koseki Y, Laskin J, Gray J, Janik A, Sweatman TW, Lothstein L: N-benzyladriamycin-14-valerate (AD 198): a non-cardiotoxic anthracycline that is cardioprotective through PKC-epsilon activation. J Pharmacol Exp Ther. 2007, 323: 658-664. 10.1124/jpet.107.126110.CrossRefPubMed

36.

Harstrick A, Vanhoefer U, Schleucher N, Schroeder J, Baumgart J, Scheulen ME, Wilke H, Seeber S: Activity of N-benzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines. Anticancer Drugs. 1995, 6: 681-685. 10.1097/00001813-199510000-00007.CrossRefPubMed

37.

Olsnes AM, Ersvaer E, Ryningen A, Paulsen K, Hampson P, Lord JM, Gjertsen BT, Kristoffersen EK, Bruserud O: The protein kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells. Br J Haematol. 2009, 145: 761-774. 10.1111/j.1365-2141.2009.07691.x.CrossRefPubMed

38.

Bilyeu JD, Panta GR, Cavin LG, Barrett CM, Turner EJ, Sweatman TW, Israel M, Lothstein L, Arsura M: Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines. Mol Pharmacol. 2004, 65: 1038-1047. 10.1124/mol.65.4.1038.CrossRefPubMed

39.

Basu A, Pal D: Two faces of protein kinase Cdelta: the contrasting roles of PKCdelta in cell survival and cell death. ScientificWorldJournal. 2010, 10: 2272-2284.CrossRefPubMed

40.

Yoshida K: PKCdelta signaling: mechanisms of DNA damage response and apoptosis. Cell Signal. 2007, 19: 892-901. 10.1016/j.cellsig.2007.01.027.CrossRefPubMed

41.

Ersvaer E, Kittang AO, Hampson P, Sand K, Gjertsen BT, Lord JM, Bruserud O: The protein kinase C agonist PEP005 (ingenol 3-angelate) in the treatment of human cancer: a balance between efficacy and toxicity. Toxins (Basel). 2010, 2: 174-194. 10.3390/toxins2010174.CrossRef

42.

Vartanian R, Masri J, Martin J, Cloninger C, Holmes B, Artinian N, Funk A, Ruegg T, Gera J: AP-1 regulates cyclin D1 and c-MYC transcription in an AKT-dependent manner in response to mTOR inhibition: role of AIP4/Itch-mediated JUNB degradation. Mol Cancer Res. 2010, 9: 115-130. 10.1186/1476-4598-9-115.CrossRefPubMedPubMedCentral

43.

Park SS, Kim JS, Tessarollo L, Owens JD, Peng L, Han SS, Tae Chung S, Torrey TA, Cheung WC, Polakiewicz RD, et al: Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice. Cancer Res. 2005, 65: 1306-1315. 10.1158/0008-5472.CAN-04-0268.CrossRefPubMed

44.

Chen S, Qiong Y, Gardner DG: A role for p38 mitogen-activated protein kinase and c-myc in endothelin-dependent rat aortic smooth muscle cell proliferation. Hypertension. 2006, 47: 252-258. 10.1161/01.HYP.0000198424.93598.6b.CrossRefPubMed

45.

Smith SM, Anastasi J, Cohen KS, Godley LA: The impact of MYC expression in lymphoma biology: beyond Burkitt lymphoma. Blood Cells Mol Dis. 2010, 45: 317-323. 10.1016/j.bcmd.2010.08.002.CrossRefPubMed

46.

Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, McAlpine D, Johns J, Scott TM, Sutherland KP, et al: Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004, 64: 2833-2839. 10.1158/0008-5472.CAN-03-2837.CrossRefPubMed

47.

Ogbourne SM, Hampson P, Lord JM, Parsons P, De Witte PA, Suhrbier A: Proceedings of the first international conference on PEP005. Anticancer Drugs. 2007, 18: 357-362. 10.1097/CAD.0b013e3280149ec5.CrossRefPubMed

48.

Challacombe JM, Suhrbier A, Parsons PG, Jones B, Hampson P, Kavanagh D, Rainger GE, Morris M, Lord JM, Le TT, et al: Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol. 2006, 177: 8123-8132.CrossRefPubMed

49.

Hampson P, Kavanagh D, Smith E, Wang K, Lord JM, Ed Rainger G: The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-delta dependent manner. Cancer Immunol Immunother. 2008, 57: 1241-1251. 10.1007/s00262-008-0458-9.CrossRefPubMed

50.

Cozzi SJ, Parsons PG, Ogbourne SM, Pedley J, Boyle GM: Induction of senescence in diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of the mitogen-activated protein kinase pathway. Cancer Res. 2006, 66: 10083-10091. 10.1158/0008-5472.CAN-06-0348.CrossRefPubMed

51.

Benhadji KA, Serova M, Ghoul A, Cvitkovic E, Le Tourneau C, Ogbourne SM, Lokiec F, Calvo F, Hammel P, Faivre S, et al: Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells. Br J Cancer. 2008, 99: 1808-1815. 10.1038/sj.bjc.6604642.CrossRefPubMedPubMedCentral

52.

Roaten JB, Kazanietz MG, Sweatman TW, Lothstein L, Israel M, Parrill AL: Molecular models of N-benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-delta. J Med Chem. 2001, 44: 1028-1034. 10.1021/jm000289v.CrossRefPubMed

53.

Barrett CM, Lewis FL, Roaten JB, Sweatman TW, Israel M, Cleveland JL, Lothstein L: Novel extranuclear-targeted anthracyclines override the antiapoptotic functions of Bcl-2 and target protein kinase C pathways to induce apoptosis. Mol Cancer Ther. 2002, 1: 469-481.PubMed

54.

Roaten JB, Kazanietz MG, Caloca MJ, Bertics PJ, Lothstein L, Parrill AL, Israel M, Sweatman TW: Interaction of the novel anthracycline antitumor agent N-benzyladriamycin-14-valerate with the C1-regulatory domain of protein kinase C: structural requirements, isoform specificity, and correlation with drug cytotoxicity. Mol Cancer Ther. 2002, 1: 483-492.PubMed

55.

Ramsay G, Evan GI, Bishop JM: The protein encoded by the human proto-oncogene c-myc. Proc Natl Acad Sci U S A. 1984, 81: 7742-7746. 10.1073/pnas.81.24.7742.CrossRefPubMedPubMedCentral

56.

Gregory MA, Hann SR: c-myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-myc in burkitt’s lymphoma cells. Mol Cell Biol. 2000, 20: 2423-2435. 10.1128/MCB.20.7.2423-2435.2000.CrossRefPubMedPubMedCentral

57.

Lameh J, Chuang LF, Israel M, Chuang RY: Mechanistic studies on N-benzyladriamycin-14-valerate (AD 198), a highly lipophilic alkyl adriamycin analog. Anticancer Res. 1988, 8: 689-693.PubMed

58.

Ganapathi R, Grabowski D, Sweatman TW, Seshadri R, Israel M: N-benzyladriamycin-14-valerate versus progressively doxorubicin-resistant murine tumours: cellular pharmacology and characterisation of cross-resistance in vitro and in vivo. Br J Cancer. 1989, 60: 819-826. 10.1038/bjc.1989.373.CrossRefPubMedPubMedCentral

59.

Lothstein L, Wright HM, Sweatman TW, Israel M: N-benzyladriamycin-14-valerate and drug resistance: correlation of anthracycline structural modification with intracellular accumulation and distribution in multidrug resistant cells. Oncol Res. 1992, 4: 341-347.PubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/481/prepub

Title: N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma
Authors: Shanique K E Edwards
Carissa R Moore
Yan Liu
Sukhdeep Grewal
Lori R Covey
Ping Xie
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-13-481

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2013

Gene-guided Gefitinib switch maintenance therapy for patients with advanced EGFR mutation-positive Non-small cell lung cancer: an economic analysis

Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia

In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells

Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells

IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer

FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

Keynote webinar | Spotlight on antibody–drug conjugates in cancer