Arsenic trioxide and bortezomib interact synergistically to induce apoptosis in chronic myelogenous leukemia cells resistant to imatinib mesylate through Bcr/Abl‑dependent mechanisms

Xu,Wenbin; Wei,Wei; Yu,Qing; Wu,Chao; Ye,Chenjing; Wu,Yingli; Yan,Hua

doi:10.3892/mmr.2014.2333

Arsenic trioxide and bortezomib interact synergistically to induce apoptosis in chronic myelogenous leukemia cells resistant to imatinib mesylate through Bcr/Abl‑dependent mechanisms

Authors:
- Wenbin Xu
- Wei Wei
- Qing Yu
- Chao Wu
- Chenjing Ye
- Yingli Wu
- Hua Yan
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Affiliations: Exclusive Medical Care Center, Rui‑Jin Hospital, Shanghai Jiao‑Tong University School of Medicine, Shanghai 200025, P.R. China, Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao‑Tong University School of Medicine, Shanghai 200025, P.R. China
Published online on: June 16, 2014 https://doi.org/10.3892/mmr.2014.2333
Pages: 1519-1524

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Abstract

Arsenic trioxide (As2O3) and the proteasome inhibitor bortezomib (BTZ) have been used successfully to treat acute promyelocytic leukemia and multiple myeloma. Their synergistic effects with other anticancer drugs have been widely studied. In this study, interactions between As2O3 and BTZ were examined in imatinib‑resistant Bcr/Abl+ (K562r) cells. Co‑treatment of K562r cells with subtoxic concentrations of As2O3 (2 µM) and BTZ (24 nM) resulted in a synergistic enhancement in growth inhibition and apoptosis, as demonstrated by increased annexin V staining. These events were associated with activation of protein kinase Cδ, poly ADP‑ribose polymerase cleavage and caspase‑3 activation, along with downregulation of Bcr/Abl mRNA and Bcr/Abl protein expression levels during apoptosis. In addition, reactive oxygen species were downregulated during combined treatment in K562r cells. Collectively, these findings suggest that BTZ and As2O3 act synergistically to induce apoptosis in K562r cells. Therefore, further studies are required to assess the potential of BTZ and As2O3 combinatory treatment of chronic myeloid leukemia, particularly using imatinib‑resistant Bcr/Abl+ clones.

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1	Schiffer CA, Hehlmann R and Larson R: Perspectives on the treatment of chronic phase and advanced phase CML and Philadelphia chromosome positive ALL(1). Leukemia. 17:691–699. 2003. View Article : Google Scholar : PubMed/NCBI
2	Voss J, Posern G, Hannemann JR, Wiedemann LM, Turhan AG, Poirel H, Bernard OA, Adermann K, Kardinal C and Feller SM: The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways. Oncogene. 19:1684–1690. 2000. View Article : Google Scholar
3	Danial NN and Rothman P: JAK-STAT signaling activated by Abl oncogenes. Oncogene. 19:2523–2531. 2000. View Article : Google Scholar : PubMed/NCBI
4	Kirchner D, Duyster J, Ottmann O, Schmid RM, Bergmann L and Munzert G: Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation. Exp Hematol. 31:504–511. 2003. View Article : Google Scholar : PubMed/NCBI
5	Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS, Akhtar AJ, Hilton J and Jones RJ: BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. Blood. 86:1148–1158. 1995.PubMed/NCBI
6	Bueno-da-Silva AE, Brumatti G, Russo FO, Green DR and Amarante-Mendes GP: Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity. Cell Death Differ. 10:592–598. 2003. View Article : Google Scholar : PubMed/NCBI
7	Amarante-Mendes GP, McGahon AJ, Nishioka WK, Afar DE, Witte ON and Green DR: Bcl-2-independent Bcr-Abl-mediated resistance to apoptosis: protection is correlated with up regulation of Bcl-xL. Oncogene. 16:1383–1390. 1998. View Article : Google Scholar : PubMed/NCBI
8	Cavo M: Proteasome inhibitor bortezomib for the treatment of multiple myeloma. Leukemia. 20:1341–1352. 2006. View Article : Google Scholar : PubMed/NCBI
9	Caravita T, de Fabritiis P, Palumbo A, Amadori S and Boccadoro M: Bortezomib: efficacy comparisons in solid tumors and hematologic malignancies. Nat Clinl Pract Oncol. 3:374–387. 2006. View Article : Google Scholar : PubMed/NCBI
10	Dai Y, Rahmani M, Pei XY, Dent P and Grant S: Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood. 104:509–518. 2004. View Article : Google Scholar
11	Yu C, Rahmani M, Conrad D, Subler M, Dent P and Grant S: The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl⁺ cells sensitive and resistant to STI571. Blood. 102:3765–3774. 2003. View Article : Google Scholar : PubMed/NCBI
12	Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z and Wang ZY: Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 89:3354–3360. 1997.PubMed/NCBI
13	Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, Jin XL, Tang W, Li XS, Xong SM, Shen ZX, Sun GL, Ma J, Zhang P, Zhang TD, Gazin C, Naoe T, Chen SJ, Wang ZY and Chen Z: In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia: As₂O₃ induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood. 88:1052–1061. 1996.PubMed/NCBI
14	Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A and Chandy M: Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 107:2627–2632. 2006. View Article : Google Scholar
15	Perkins C, Kim CN, Fang G and Bhalla KN: Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L). Blood. 95:1014–1022. 2000.
16	Porosnicu M, Nimmanapalli R, Nguyen D, Worthington E, Perkins C and Bhalla KN: Co-treatment with As₂O₃ enhances selective cytotoxic effects of STI-571 against Brc-Abl-positive acute leukemia cells. Leukemia. 15:772–778. 2001.PubMed/NCBI
17	Potin S, Bertoglio J and Bréard J: Involvement of a Rho-ROCK-JNK pathway in arsenic trioxide-induced apoptosis in chronic myelogenous leukemia cells. FEBS Lett. 581:118–124. 2007. View Article : Google Scholar : PubMed/NCBI
18	Yan H, Wang YC, Li D, Wang Y, Liu W, Wu YL and Chen GQ: Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cdelta. Leukemia. 21:1488–1495. 2007. View Article : Google Scholar
19	Circu ML and Aw TY: Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med. 48:749–762. 2010. View Article : Google Scholar : PubMed/NCBI
20	Chou WC, Jie C, Kenedy AA, Jones RJ, Trush MA and Dang CV: Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci USA. 101:4578–4583. 2004. View Article : Google Scholar : PubMed/NCBI
21	Stepnik M, Ferlińska M, Smok-Pieniążek A, Gradecka-Meesters D, Arkusz J and Stańczyk M: Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines. Med Oncol. 29:1161–1172. 2012.
22	Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN and Sawyers CL: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 293:876–880. 2001. View Article : Google Scholar : PubMed/NCBI
23	Radujkovic A, Schad M, Topaly J, Veldwijk MR, Laufs S, Schultheis BS, Jauch A, Melo JV, Fruehauf S and Zeller WJ: Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL - Inhibition of P-glycoprotein function by 17-AAG. Leukemia. 19:1198–1206. 2005. View Article : Google Scholar : PubMed/NCBI
24	Li QF, Yan J, Zhang K, Yang YF, Xiao FJ, Wu CT, Wang H and Wang LS: Bortezomib and sphingosine kinase inhibitor interact synergistically to induces apoptosis in BCR/ABl⁺ cells sensitive and resistant to STI571 through down-regulation Mcl-1. Biochem Biophys Res Commun. 405:31–36. 2011. View Article : Google Scholar : PubMed/NCBI
25	Wen J, Feng Y, Huang W, Chen H, Liao B, Rice L, Preti HA, Kamble RT, Zu Y, Ballon DJ and Chang CC: Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition. Leuk Res. 34:85–92. 2010. View Article : Google Scholar : PubMed/NCBI
26	Canestraro M, Galimberti S, Savli H, Palumbo GA, Tibullo D, Nagy B, Guerrini F, Piaggi S, Cine N, Metelli MR and Petrini M: Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Gene Cytogenet. 199:110–120. 2010. View Article : Google Scholar
27	He Y, Yang JM, Wang JM, Zhou H, Lü SQ and Hu XX: Synergistic effects of arsenic trioxide and proteasome inhibitor bortezomib on apoptosis induction in Raji cell line. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 16:794–798. 2008.(In Chinese).
28	Ruemmele FM, Dionne S, Qureshi I, Sarma DS, Levy E and Seidman EG: Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP). Cell Death Differ. 6:729–735. 1999. View Article : Google Scholar : PubMed/NCBI
29	Fernandez-Luna JL: Bcr-Abl and inhibition of apoptosis in chronic myelogenous leukemia cells. Apoptosis. 5:315–318. 2000. View Article : Google Scholar : PubMed/NCBI
30	Bianchini M, De Brasi C, Gargallo P, Gonzalez M, Bengió R and Larripa I: Specific assessment of BCR-ABL transcript overexpression and imatinib resistance in chronic myeloid leukemia patients. Eur J Haematol. 82:292–300. 2009. View Article : Google Scholar : PubMed/NCBI
31	Wei W, Huang H, Zhao S, Liu W, Liu CX, Chen L, Li JM, Wu YL and Yan H: Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-κB inhibition and Bcr/Abl protein deletion. Apoptosis. 18:1060–1070. 2013.
32	Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T, Greenfield EA, Salgia R and Griffin JD: The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem. 275:24273–24278. 2000. View Article : Google Scholar : PubMed/NCBI
33	Stein SJ and Baldwin AS: NF-κB suppresses ROS levels in BCR-ABL(+) cells to prevent activation of JNK and cell death. Oncogene. 30:4557–4566. 2011.
34	Naughton R, Quiney C, Turner SD and Cotter TG: Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway. Leukemia. 23:1432–1440. 2009. View Article : Google Scholar : PubMed/NCBI