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01-10-2010 | Original Article

The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo

Authors: Scott Ackler, Michael J. Mitten, Kelly Foster, Anatol Oleksijew, Marion Refici, Stephen K. Tahir, Yu Xiao, Christin Tse, David J. Frost, Stephen W. Fesik, Saul H. Rosenberg, Steven W. Elmore, Alexander R. Shoemaker

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2010

Abstract

Purpose

This study was designed to test the ability of the Bcl-2 family inhibitor ABT-263 to potentiate commonly used chemotherapeutic agents and regimens in hematologic tumor models.

Methods

Models of B-cell lymphoma and multiple myeloma were tested in vitro and in vivo with ABT-263 in combination with standard chemotherapeutic regimens, including VAP, CHOP and R-CHOP, as well as single cytotoxic agents including etoposide, rituximab, bortezomib and cyclophosphamide. Alterations in Bcl-2 family member expression patterns were analyzed to define mechanisms of potentiation.

Results

ABT-263 was additive with etoposide, vincristine and VAP in vitro in the diffuse large B-cell lymphoma line (DLBCL) DoHH-2, while rituximab potentiated its activity in SuDHL-4. Bortezomib strongly synergized with ABT-263 in the mantle cell lymphoma line Granta 519. Treatment of DoHH-2 with etoposide was associated with an increase in Puma expression, while bortezomib upregulated Noxa expression in Granta 519. Combination of ABT-263 with cytotoxic agents demonstrated superior tumor growth inhibition and delay in multiple models versus cytotoxic therapy alone, along with significant improvements in tumor response rates.

Conclusions

Inhibition of the Bcl-2 family of proteins by ABT-263 enhances the cytotoxicity of multiple chemotherapeutics in hematologic tumors and represents a promising addition to the therapeutic arsenal for treatment of these diseases.

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SEER Surveillance Epidemiology and End Results [homepage on the internet]. Bethesda: National Cancer Institute; c1973-2007 [updated 18 Dec 2007; cited 2 Jan 2008]. Cancer Stats Fact Sheet, Non-Hodgkin Lymphoma [top of page]. Available from: http://seer.cancer.gov/statfacts/html/nhl.html

Cvetkovic RS, Perry CM (2006) Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs 66:791–820CrossRefPubMed

Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14:1649–1657CrossRefPubMed

Utecht KN, Kolesar J (2008) Bortezomib: a novel chemotherapeutic agent for hematologic malignancies. Am J Health Syst Pharm 65:1221–1231CrossRefPubMed

Wei MC (2004) Bcl-2-related genes in lymphoid neoplasia. Int J Hematol 80:205–209CrossRefPubMed

Reed JC (1997) Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 34:9–19PubMed

Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226:1097–1099CrossRefPubMed

Agarwal B, Naresh KN (2002) Bcl-2 family of proteins in indolent B-cell non-Hodgkin’s lymphoma: study of 116 cases. Am J Hematol 70:278–282CrossRefPubMed

Harada N, Hata H, Yoshida M et al (1998) Expression of Bcl-2 family of proteins in fresh myeloma cells. Leukemia 12:1817–1820CrossRefPubMed

10.

Alizadeh AA, Eisen MB, Davis RE et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511CrossRefPubMed

11.

Packham G, Stevenson FK (2005) Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia. Immunology 114:441–449CrossRefPubMed

12.

Tu Y, Renner S, Xu F et al (1998) Bcl-X expression in multiple myeloma: possible indicator of chemoresistance. Cancer Res 58:256–262PubMed

13.

Fukumi S, Horiguchi-Yamada J, Nakada S, Nagai M, Ohno T, Yamada H (2000) Differential responses of Bcl-2 family genes to etoposide in chronic myeloid leukemia K562 cells. Mol Cell Biochem 206:43–50CrossRefPubMed

14.

Floros KV, Thomadaki H, Florou D, Talieri M, Scorilas A (2006) Alterations in mRNA expression of apoptosis-related genes BCL2, BAX, FAS, caspase-3, and the novel member BCL2L12 after treatment of human leukemic cell line HL60 with the antineoplastic agent etoposide. Ann N Y Acad Sci 1090:89–97CrossRefPubMed

15.

Belhoussine R, Morjani H, Gillet R, Palissot V, Manfait M (1999) Two distinct modes of oncoprotein expression during apoptosis resistance in vincristine and daunorubicin multidrug-resistant HL60 cells. Adv Exp Med Biol 457:365–381PubMed

16.

Liu FT, Agrawal SG, Gribben JG et al (2008) Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL. Blood 111:2797–2805CrossRefPubMed

17.

Gomez-Bougie P, Wuilleme-Toumi S, Menoret E et al (2007) Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. Cancer Res 67:5418–5424CrossRefPubMed

18.

Byrd JC, Kitada S, Flinn IW et al (2002) The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood 99:1038–1043CrossRefPubMed

19.

Tse C, Shoemaker AR, Adickes J et al (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68:3421–3428CrossRefPubMed

20.

Ackler S, Xiao Y, Mitten MJ et al (2008) ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther 7:3265–3274CrossRefPubMed

21.

Lock R, Carol H, Houghton PJ et al (2008) Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer 50:1181–1189CrossRefPubMed

22.

Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A (2007) Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 117:112–121CrossRefPubMed

23.

Paoluzzi L, Gonen M, Bhagat G et al (2008) The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood 112:2906–2916CrossRefPubMed

24.

Kang MH, Kang YH, Szymanska B et al (2007) Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood 110:2057–2066CrossRefPubMed

25.

Mohammad RM, Wang S, Aboukameel A et al (2005) Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-xL [(-)-gossypol] against diffuse large cell lymphoma. Mol Cancer Ther 4:13–21PubMed

26.

Stel AJ, Ten Cate B, Jacobs S et al (2007) Fas receptor clustering and involvement of the death receptor pathway in rituximab-mediated apoptosis with concomitant sensitization of lymphoma B cells to fas-induced apoptosis. J Immunol 178:2287–2295PubMed

27.

Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55CrossRefPubMed

28.

Shoemaker AR, Oleksijew A, Bauch J et al (2006) A small-molecule inhibitor of Bcl-xL potentiates the activity of cytotoxic drugs in vitro and in vivo. Cancer Res 66:8731–8739CrossRefPubMed

29.

Sladek NE (1988) Metabolism of oxazaphosphorines. Pharmacol Ther 37:301–355CrossRefPubMed

30.

Mohammad RM, Al-Katib A, Aboukameel A, Doerge DR, Sarkar F, Kucuk O (2003) Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Mol Cancer Ther 2:1361–1368PubMed

31.

Greco FA (1999) Oral etoposide in lymphoma. Drugs 58(Suppl 3):35–41CrossRefPubMed

32.

Tahir SK, Yang X, Anderson MG et al (2007) Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res 67:1176–1183CrossRefPubMed

33.

Lin X, Morgan-Lappe S, Huang X et al (2007) ‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-xL inhibitor ABT-737. Oncogene 26:3972–3979CrossRefPubMed

34.

Konopleva M, Contractor R, Tsao T et al (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375–388CrossRefPubMed

35.

van Delft MF, Wei AH, Mason KD et al (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399CrossRefPubMed

36.

Mandelin AM II, Pope RM (2007) Myeloid cell leukemia-1 as a therapeutic target. Expert Opin Ther Targets 11:363–373CrossRefPubMed

37.

Kutuk O, Arisan ED, Tezil T, Shoshan MC, Basaga H (2009) Cisplatin overcomes Bcl-2-mediated resistance to apoptosis via preferential engagement of Bak: critical role of Noxa-mediated lipid peroxidation. Carcinogenesis 30:1517–1527CrossRefPubMed

38.

Olejniczak SH, Hernandez-Ilizaliturri FJ, Clements JL, Czuczman MS (2008) Acquired resistance to rituximab is associated with chemotherapy resistance resulting from decreased Bax and Bak expression. Clin Cancer Res 14:1550–1560CrossRefPubMed

39.

Jazirehi AR, Vega MI, Bonavida B (2007) Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy. Cancer Res 67:1270–1281CrossRefPubMed

40.

Wobser M, Voigt H, Eggert AO et al (2007) Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma. Br J Cancer 96:1540–1543CrossRefPubMed

41.

Mohammad RM, Wall NR, Dutcher JA, Al-Katib AM (2000) The addition of bryostatin 1 to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy improves response in a CHOP-resistant human diffuse large cell lymphoma xenograft model. Clin Cancer Res 6:4950–4956PubMed

42.

Reed JC, Kitada S, Takayama S, Miyashita T (1994) Regulation of chemoresistance by the Bcl-2 oncoprotein in non-Hodgkin’s lymphoma and lymphocytic leukemia cell lines. Ann Oncol 5(Suppl 1):61–65PubMed

43.

Minn AJ, Rudin CM, Boise LH, Thompson CB (1995) Expression of Bcl-xL can confer a multidrug resistance phenotype. Blood 86:1903–1910PubMed

44.

Tu Y, Xu FH, Liu J et al (1996) Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide. Blood 88:1805–1812PubMed

Title: The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo
Authors: Scott Ackler
Michael J. Mitten
Kelly Foster
Anatol Oleksijew
Marion Refici
Stephen K. Tahir
Yu Xiao
Christin Tse
David J. Frost
Stephen W. Fesik
Saul H. Rosenberg
Steven W. Elmore
Alexander R. Shoemaker
Publication date: 01-10-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1232-1

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Abstract

Purpose

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Results

Conclusions

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